EA003780B1 - Phenylphenanthridines with pde-iv inhibiting activity - Google Patents

Abstract

1. A compound of formula I in which R1 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, R2 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, or in which R1 and R2 together are a C1-2 alkylenedioxy group, R3 is hydrogen or C1-4 alkyl, R31 is hydrogen or C1-4, or in which R3 and R31 together are a C1-4 alkylene group, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen, R51 is hydrogen, or in which R5 and R51 together represent an additional bond, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, S(O)2-aryl, O-S(O)2-R11, pyrrolidin-1-yl, pyrrolidin-1-yl-2-one, pyrrolidin-1-yl-2,5-dione, piperidin-1-yl, piperidin-1-yl-2-one or piperidin-1-yl-2,6-dione, where R7 is C3-7 cycloalkyl, C3-7 cycloalkylmethyl, C1-4 alkoxy- C1-4 alkyl, aryl or phenyl- C1-4 alkyl, R8 is hydrogen, C1-4 alkyl, C1-4 alkylcarbonyl, arylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl, R9 is C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, R10 is hydroxyl, halogen, cyano, carboxyl, C4-1 alkoxy, phenoxy, C1-4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-4 alkylaminocarbonyl, N(R15)R16 or C1-4 alkylcarbonylamino, and R11 is C1-4 alkyl, amino, mono- or di-C1-4 alkylamino or aryl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylcarbonyloxy or aminocarbonyl, R13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, phenyl, phenyl-C1-4 alkyl, C(O)-OR14, C(O)-N (R15)R16, N(R17)R18, S(O)2-R19, S(O)2-N(R15)R16 or has one of the meanings of R6, where R14 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R15 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R16 is hydrogen, C1-4 alkyl, C3-7 -cycloalkyl, C3-7 cycloalkylmethyl or aryl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, represent a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical, R17 is hydrogen, C1-4 alkyl, S(O)2-R19 or S(O)2-aryl, R18 is C1-4 alkyl, C1-4 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C3-7 cycloalkylmethylcarbonyl, S(O)2-R19 or S(O)2-aryl, and R19 is C1-4 alkyl, R20 is hydrogen, hydroxyl, halogen, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, CH2-R10, carboxyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylcarbonylamino or aminocarbonyl, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 2. A compound of formula I as claimed in claim 1, in which R1 is C1-2 alkoxy, C3-5 cycloalkoxy, C3-5 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-2 alkoxy, R2 is C1-2 alkoxy, C3-5 cycloalkoxy, C3-5 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-2 alkoxy, R3 is hydrogen, R31 is hydrogen, R4 is hydrogen or C1-2 alkyl, R5 is hydrogen, R51 is hydrogen, or in which R5 and R51 together represent an additional bond, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, SO2-aryl, O-S(O)2-R11, pyrrolidin-1-yl, pyrrolidin-1-yl-2-one or pyrrolidin-1-yl-2,5-dione, Where R7 is C3-7 cycloalkyl, C3-7 cycloalkylmethyl, C1-4 alkoxy- C1-4 alkyl, aryl or phenyl- C1-4 alkyl, R8 is hydrogen, C1-4 alkyl, acetyl, phenylcarbonyl, trifluoromethyl or phenyl, R9 is C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, R10 is halogen, carboxyl, C1-4 alkoxy, phenoxy, C1-4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-4 alkylaminocarbonyl, N(R15)R16 or C1-4 alkylcarbonylamino, and R11 is C1-4 alkyl, mono- or di- C1-4 alkylamino or aryl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is halogen, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl or C1-4 alkoxy, R13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, phenyl, phenyl- C1-4 alkyl, C(O)-OR14, C(O)-N(R15)R16, N(R17)R18, S(O)2-R19, S(O)2-N(R15)R16 or has one of the meanings of R6, where R14 is hydrogen or C1-4 alkyl, R15 is hydrogen or C1-4 alkyl, R16 is hydrogen, C1-4 alkyl or aryl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, are a 1-piperidyl, 1-piperazinyl, 1-methylpiperazin-4-yl or 4-morpholinyl radical, R17 is hydrogen, C1-4 alkyl, S(O)2-R19 or S(O)2-aryl, R18 is C1-4 alkyl, C1-4 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C3-7 cycloalkylmethylcarbonyl, S(O)2-R19 or S(O)2-aryl, and R19 is C1-4 alkyl, R20 is hydrogen, hydroxyl, halogen, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkyl-methoxy, carboxyl, C1-4 alkoxycarbonyl or C1-4 alkylcarbonyloxy, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 3. A compound of formula I as claimed in claim 1, in which R1 is C1-2 alkoxy, R2 is C1-2 alkoxy, R3, R31, R4, R5 and R51 are hydrogen, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, S(O)2-phenyl, O-S(O)2-R11, pyrrolidin-1-yl, pyrrolidin-1-yl-2-one or pyrrolidin-1-yl-2,5-dione, where R7 is C3-5 cycloalkyl, C3-5 cycloalkylmethyl, C1-2 alkoxy- C1-2 alkyl, aryl or phenyl- C1-2 alkyl, R8 is phenyl, R9 is C1-4 alkyl, cycloalkylmethyl, 1-piperidinyl or aryl, R10 is halogen, C1-4 alkoxycarbonyl or N(R15)R16, and R11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is C1-4 alkyl, C1-4 alkoxy, halogen, nitro or cyano, R15 is C1-4 alkyl, and R16 is C1-4 alkyl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, are a 1-piperidinyl, 1-piperazinyl, 1-methylpiperazin-4-yl or 4-morpholinyl radical, and in which eitherR13 is hydrogen, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-2 alkoxy, or C1-4 alkylcarbonylamino and R20 is hydrogen, or R13 is hydrogen and R20 is C3-5 cycloalkoxy or C3-5 cycloalkylmethoxy, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 4. A compound of formula I as claimed in claim 1, in which R1 is C1-2 alkoxy, R2 is C1-2 alkoxy, R3, R31, R4, R5 and R51 are hydrogen, R6 is O-R7, S-R8, C(O)-R9, CH2-R10, S(O)2-phenyl, O-S(O)2-R11, pyrrolidin-1-yl or pyrrolidin-1-yl-2-one, where R7 is cyclobutyl, cyclopentyl, cyclopropylmethyl, 2-methoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl or pyridyl, R8 is phenyl, R9 is methyl, ethyl, isobutyl, cyclopropylmethyl, 1-piperidinyl or aryl, R10 is methoxycarbonyl, morpholin-4-yl or 1-methylpiperazin-4-yl, and R11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or R12-substituted phenyl, in which R12 is methoxy, halogen, nitro or cyano, and in which either R13 is hydrogen, methoxy, ethoxy, difluoromethoxy or acetylamino and R20 is hydrogen, or R13 is hydrogen and R20 is cyclopropylmethoxy, or a pharmaceutically acceptable salt, an N-oxide, or a salt of an N-oxide of this compound. 5. A compound of formula I as claimed in claim 1, in which R1 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, R2 is hydroxyl, C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-4 alkoxy, or in which R1 and R2 together are a C1-2 alkylenedioxy group, R3 is hydrogen or C1-4 alkyl, R31 is hydrogen or C1-4 alkyl, or in which R3 and R31 together are a C1-4 alkylene group, R4 is hydrogen or C1-4 alkyl, R5 is hydrogen, R51 is hydrogen, or in which R5 and R51 together are an additional bond, R6 is O-R7, S-R8, C(O)-R9, CH2-R10 or O-S(O)2-R11, where R7 is C3-7 cycloalkyl, C3-7 cycloalkylmethyl, aryl or phenyl- C1-4 alkyl, R8 is hydrogen, C1-4 alkyl, C1-4 alkylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl, R9 is C1-4 alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, R10 is hydroxyl, halogen, cyano, carboxyl, C1-4 alkoxy, phenoxy, C1-4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-4 alkylaminocarbonyl, N(R15)R16 or C1-4 alkylcarbonylamino, and R11 is C1-4 alkyl, amino, mono- or di-C1-4 alkylamino or aryl, aryl is phenyl, pyridyl or R12-substituted phenyl, where R12 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylcarbonyloxy or aminocarbonyl, R13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, phenyl, phenyl- C1-4 alkyl, C(O)-OR14, C(O)-N(R15)R16, N(R17)R18, S(O)2-R19, S(O)2-N(R15)R16 or has one of the meanings of R6, where R14 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R15 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkylmethyl, R16 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl or aryl, or where R15 and R16, together and including the nitrogen atom to which both are bonded, are a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical, R17 is hydrogen, C1-4 alkyl, S(O)2-R19 or S(O)2-aryl, R18 is C1-4 alkyl, C1-4 alkylcarbonyl or S(O)2-R19 or S(O)2-aryl, and R19 is C1-4 alkyl, R20 is hydrogen, hydroxyl, halogen, nitro, amino, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, completely or predominantly fluorine-substituted C1-4 alkoxy, C3-7 cycloalkoxy, C3-7 cycloalkylmethoxy, CH2-R10,

Description

The scope of the invention

The invention relates to new 6-phenylphenanthridines, which are used in the pharmaceutical industry for the manufacture of drugs.

Known Information Related to the Prior Art

In Sit.Veg. 1939, 72, 675-677, 1Cet. 8os., 1956, 4280-4283 and 1.Siesc.8os. (C), 1971, 1805, the synthesis of 6-phenylphenanthridines is described. In XVO 97/28131 and νθ 97/35854, 6-phenyl and 6 pyridylphenanthridines are described as PDE4 inhibitors.

Description of the invention

It was found that the new 6-phenylphenanthridines, which are described in more detail below, are different from the previously known 6-phenylphenanthridines by another substitution pattern on the 6-phenyl ring and have unexpected and especially valuable properties.

Thus, an object of the invention are compounds of formula I

wherein K.1 is hydroxyl, C1-C ₄ alkoxy, C ₃ -C ₇ cycloalkoxy, Cs-C ₇ cycloalkylmethoxy or completely or predominantly fluorine-substituted _C1-C4 alkoxy,

R2 is hydroxy, _C1-C4 alkoxy, C3-S7tsikloalkoksi, C3-S7tsikloalkilmetoksi or completely or predominantly fluorine-substituted C ₁ -C ₄ alkoxy, or in which

K1 and K2 together represent a CS2 alkylenedioxy group,

K3 is a hydrogen atom or C1C4 alkyl,

K31 denotes a hydrogen atom or C1C4 alkyl, or in which

K3 and K31 together represent a CS4 alkylene group,

K4 is a hydrogen atom or CS4 alkyl,

K5 represents a hydrogen atom,

K51 denotes a hydrogen atom, or in which

K5 and K51 together denote an additional bond,

K6 is O-K7, 8-K8, C (O) -K9, CH2K10, 8 (O) ₂ -aryl, O-8 (O) ₂ -K11, pyrrolidin-1-yl, pyrrolidin-1-yl-2 -one, pyrrolidin-1-yl-2,5-dione, piperidin-1-yl, piperidin-1-yl-2-one or piperidin-1-yl-2,6-dione, where

C7 denotes a C ₃ -C ₇ cycloalkyl, C _{3 to} C ₇ cycloalkylmethyl, C 1 -C ₄ alkoxy-C 1 -C ₄ alkyl, aryl or _phenyl-C1-C4 alkyl,

K8 represents a hydrogen atom, C | C ₄ alkyl, C 1 -C ₄ alkylcarbonyl, arylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl,

R9 is C1-C ₄ alkyl, C ₃ C ₇ cycloalkyl, C ₃ -C ₇ cycloalkylmethyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4metilpiperazinil, 4-morpholinyl or aryl,

K10 is hydroxyl, halogen atom, cyano, carboxyl, C1-C4 alkoxy, phenoxy, C1-C4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-C4 alkylaminocarbonyl,

Ν (Κ15) Κ16 or _C1-C4 alkylcarbonylamino, and

K11 is _C1-C4 alkyl, amino, mono- or di-C ₁ -C ₄ alkylamino or aryl, aryl is phenyl, pyridyl or phenyl K12zameschenny where

K12 denotes hydroxyl, a halogen atom, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylcarbonyloxy or aminocarbonyl,

K13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1C ₄ alkyl, trifluoromethyl, C1C ₄ alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, phenyl, phenyl-C1C ₄ alkyl, C ( O) OK14, C (O) ^ (K.15) K16,

Ν (Κ17) Κ18, 8 (O) ₂ -K19, 8 (O) ₂ - ^ K15) K16 or has one of the values of K6, where

K14 represents a hydrogen atom, C1-4 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylmethyl,

K15 represents a hydrogen atom, CS4 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylmethyl,

K16 represents a hydrogen atom, CS4 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylmethyl or aryl, or when

K15 and K16 together and including the nitrogen atom to which they are bonded, represent 1 pyrrolidinyl, 1-piperidinyl, 1 piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical,

K17 is hydrogen, C / C ₄ alkyl, 8 (O) -K19 ₂ or 8 (O) ₂ -aryl,

K18 is _C1-C4 alkyl, _{C1-C4-alkylcarbonyl,} C3-S7tsikloalkilkarbonil, S3S tsikloalkilmetilkarbonil _7, 8 (OH) ₂ or -K19

8 (O) ₂ -aryl, and

K19 is _C1-C4 alkyl,

K20 is hydrogen, hydroxyl, halogen, nitro, amino, C1C ₄ alkyl, trifluoromethyl, C1C ₄ alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, C3-S7tsikloalkoksi, C3-S7tsikloalkilmetoksi, CH ₂ -K10, carboxyl, CS4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy,

C-Cdalkylcarbonylamino group or amino carbonyl, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds.

The term _C1-C4 alkyl denotes straight-chain or branched alkyl radical comprising from 1 to 4 carbon atoms. Examples that may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, and preferably ethyl and methyl radicals.

The term C ₁ -C ₄ alkoxy refers to radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical comprising from 1 to 4 carbon atoms. Examples that may be mentioned are butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, and preferably ethoxy and methoxy radicals.

The term C ₃ -C ₇ cycloalkoxy means cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

The term C ₃ -C ₇ cycloalkylmethoxy means cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.

Examples of fully or predominantly fluoro-substituted C ₁ -C ₄ alkoxy include 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy, 1,2,2-trifluoroethoxy, in particular 1,1,2,2-tetrafluoroethoxy, 2 , 2,2-trifluoroethoxy, trifluoromethoxy, and preferably difluoromethoxy radicals. In this regard, the concept mainly serves as an indication that more than half of the hydrogen atoms are replaced by fluorine atoms.

Examples of C ₁ -C ₂ alkylenedioxy are methylenedioxy (—O — CH ₂ —O—) and ethylenedioxy radicals (—O — CH ₂ —CH ₂ —O—).

If KZ and K31 together denote C ₁ C ₄ alkylene, the carbon atoms at positions 1 and 4 in the compounds of formula I are linked together by a C ₁ -C ₄ alkylene bridge, and the term C ₁ -C ₄ alkylene means straight-chain or branched alkylene radicals containing from 1 to 4 carbon atoms. Examples that may be mentioned are methylene (-CH2-), ethylene (-CH2-CH2-), trimethylene (-CH ₂ CH ₂ -CH ₂ -), 1,2 dimethylethylene [-CH (CH ₃ ) -CH ( CH ₃ ) -] and isopropylidene [-C (CH ₃ ) ₂ -] radicals.

If K5 and K51 together denote an additional bond, the carbon atoms in positions 2 and 3 in the compounds of formula I are linked by a double bond.

In the scope of the invention, a halogen atom means a bromine, chlorine or fluorine atom.

The term C ₃ -C ₇ cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

The term C ₃ -C ₇ cycloalkylmethyl means a methyl radical which is substituted by one or more of the aforementioned C3C7 cycloalkyl radicals. As preferred C3-C5 cycloalkylmethyl radicals, mention may be made of cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl.

The term C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl refers to the aforementioned C ₁ -C ₄ alkyl radicals which are substituted by one of the aforementioned C ₁ -C ₄ alkoxy radicals. Examples that may be mentioned are methoxymethyl, methoxyethyl and isopropoxyethyl radicals.

By phenyl-C--Cлом alkyl means one of the aforementioned phenyl-substituted C--Cалки alkyl radicals. Examples that may be mentioned are phenethyl and benzyl radicals.

By C ₁ -C ₄ alkylcarbonyl is meant a radical which, in addition to the carbonyl group, contains one of the aforementioned C ₁ -C ₄ alkyl radicals. An example is the acetyl radical.

The term C ₃ -C ₇ cycloalkylcarbonyl means a radical which, in addition to the carbonyl group, contains one of the above C ₃ -C ₇ cycloalkyl radicals. An example that can be mentioned is the cyclopentylcarbonyl radical.

By C ₃ -C ₇ cycloalkylmethylcarbonyl means a radical which, in addition to the carbonyl group, contains one of the above C3-C7 cycloalkylmethyl radicals. As an example, mention may be made of a cyclopropylmethyl carbonyl radical.

The term C ₁ -C ₄ alkoxycarbonyl means a carbonyl group to which one of the above C ₁ -C ₄ alkoxy radicals is bound. Examples that may be mentioned are methoxycarbonyl [CH ₃ O — C (O) -] and ethoxycarbonyl [CH ₃ CH ₂ O — C (O) -] radicals.

By C ₁ -C ₄ alkylcarbonyloxy is meant a carbonyloxy group to which one of the abovementioned C 1-4 alkyl radicals is bound. An example that can be mentioned is the acetoxy radical [CH 3 C (O) —O—].

In addition to the carbonyl group, mono- or di-C ₁ -C ₄ alkylaminocarbonyl radicals contain one of the above mono- or di-C ₁ -C ₄ alkylamino radicals. Examples that may be mentioned are Ν-methyl-, Ν, Ν-dimethyl-, Ν-ethyl-, Ν-propyl-, Ν, Ν-diethyl- and Ν-isopropylaminocarbonyl radicals.

In addition to the nitrogen atom, mono- or di-C 1 C ₄ alkylamino radicals include one or two of the above C ₁ to C ₄ alkyl radical.

Di-C ₁ -C ₄ alkylamino radicals, in particular dimethyl, diethyl and diisopropylamine radicals, are preferred.

As examples of C ₁ -C ₄ alkylcarbonylamine radicals, mention may be made of the propionylamine [C ₃ H ₇ C (O) IN-] and acetylamine [CH ₃ C (O) IN-] radicals.

Examples of phenyl radicals substituted with KB, K13 and B20. which may be mentioned are 3-phenoxyphenyl, 4-phenoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,

3- phenethoxyphenyl, 4-phenethoxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3methoxyphenyl, 3-benzyloxy-5-methoxyphenyl,

4-benzyloxy-3-cyclopropylmethoxyphenyl, 3 - cyclopentyloxyphenyl, 4-cyclopentyloxyphenyl, 4-cyclohexyloxyphenyl, 3-cyclohexyloxyphenyl, 3-cyclopropylmethoxyphenyl, 4-cyclopropylmethoxyphenyl, 3-cyclopropylmethoxy-4-methoxyphenyl, 3-4-cyclopropylmethyl cyclopropylmethoxy-4-ethoxyphenyl, 4-cyclopropylmethoxy-3-methoxyphenyl, 3-cyclopropylmethoxy-5-methoxyphenyl, bis-3,4-cyclopropylmethoxyphenyl, bis-3,5-cyclopropylmethoxyphenyl, 3,4-dicyclopentyloxyphenyl, 3-cyclopentyloxy-4- methoxyphenyl, 4-cyclopentyloxy-3-methoxyphenyl, 3-cyclo propyl methoxy

4- cyclopentyloxyphenyl, 3-cyclopentyloxy-

5-methoxyphenyl, 4-cyclopropylmethoxy-3-cyclopentyloxyphenyl, 3-cyclobutyloxy-4methoxyphenyl, 4- (3-hydroxyphenoxy) phenyl, 4 (4-hydroxyphenoxy) phenyl, 3-methoxyethoxy-4methoxyphenyl, 3-cyclopropylmethoxy-4acetylaminophenyl 4 , 4-ethylthiophenyl, 2-methylthiophenyl, 4-methylthiophenyl, 4-trifluoromethylthiophenyl, 4-methylthio-3 nitrophenyl, 4-phenylthiophenyl, 3-phenylthiophenyl, 2-methoxy-4-methylthiophenyl, 4 - [(4chlorophenyl) thio] -3- nitrophenyl, 3-methylsulfonyloxyphenyl, 4-methylsulfonyloxyphenyl, 3- (p-toluenesulfonyloxy) phenyl, 4- (p-toluenesulfonyloxy) phenyl, 4 - [(4-fluoropheni ) sulfonyloxy] phenyl, 3 - [(4-fluorophenyl) sulfonyloxy] -4-nitrophenyl, 3 - [(4-chlorophenyl) sulfonyloxy] phenyl, 4 - [(4-chlorophenyl) sulfonyloxy] phenyl, 4 - [(4- chlorophenyl) sulfonyloxy] phenyl, 4 - [(4-bromophenyl) sulfonyloxy] phenyl, 4- (pyrid-4-ylcarbonyl) phenyl, 4- (4carboxybenzoyl) phenyl, 4- (2-carboxybenzoyl) phenyl, 4- (2- bromobenzoyl) phenyl, 4- (3-bromobenzoyl) phenyl, 4- (3-methoxybenzoyl) phenyl, 4 (4-methoxybenzoyl) phenyl, 2-benzoylphenyl, 3 benzoylphenyl, 4-benzoylphenyl, 4- (4-chlorobenzoyl) phenyl, 4 - (3-chlorobenzoyl) phenyl, 4- (4-cyanobenzoyl) phenyl, 4- (4-nitrobenzoyl) phenyl, 4- (4-methylbenzoyl) phenyl, 3-acetylphe nyl, 4acetylphenyl, 4-ethylcarbonylphenyl, 4-isobutylcarbonylphenyl, 4-cyclopropylmethylcarbonylphenyl, 3,4-diacetylphenyl, 3,5 diacetylphenyl, 5-acetyl-2-hydroxyphenyl, 3 (piperidin-1-ylcarbonyl) phenyl, 4- (p

1-ylcarbonyl) phenyl, 4-methoxycarbonylmethyl-phenyl, 4- (morpholin-4-ylmethyl) phenyl, 4- (4methylpiperazin-1-ylmethyl) phenyl, 3-dimethylsulfamoyloxyphenyl, 4-dimethylsulfamoyloxyphenyl, 3-chloro-4-dimethyl 3-methylsulfonyloxy-4-nitrophenyl, 4-chloromethylphenyl, 3-chloromethylphenyl, 3 (phenylsulfonyl) phenyl, 4- (phenylsulfonyl) phenyl, 3- (4-methoxyphenoxy) phenyl, 3- (pyrid-4yloxy) phenyl, 4- ( pyrid-4-yloxy) phenyl, 3pyrrolidinyl-4-methoxyphenyl, 3- (pyrrolidin-

2-on-1-yl) phenyl and 3- (pyrrolidin-2,5-dion-1yl) phenyl.

Depending on the substituents, all possible salts of the compounds of formula I are either acid addition salts or base salts. Specifically, pharmaceutically acceptable salts of mineral and organic acids and bases commonly used in pharmaceuticals can be mentioned. These salts, on the one hand, include water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, Ό- gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid a, stearic acid, toluenesulfonic acid, methanesulfonic acid and 3-hydroxy-2-naphthoic acid; moreover, in the preparation of salts, acids can be used depending on which acid is of interest, mono- or polybasic, and depending on which salt necessary, whether it is in equimolar or different quantitative ratio.

On the other hand, salts with bases are also acceptable. Examples of salts with bases that can be mentioned include alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidine salts, moreover, in the preparation of the salt, the base is used in an equimolar or different quantitative ratio.

Pharmaceutically unacceptable salts that may initially be prepared, for example, as products of a process for preparing the compounds of the invention on an industrial scale, are converted to pharmaceutically acceptable salts by processes known to those skilled in the art.

One skilled in the art will recognize that the compounds of the invention and their salts, when isolated, for example, in crystalline form, may include various amounts of solvents. Thus, the scope of the invention also covers all solvates and, in particular, all hydrates of compounds of formula I, as well as all solvates and, in particular, all hydrates of salts of compounds of formula I.

In one embodiment (Embodiment A) of the invention, there are provided compounds of formula I in which

R1 is _C1-C2 alkoxy, C ₃ C ₅ cycloalkoxy, C ₃ -C ₅ cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-S2alkoksi,

K2 is C ₁ -C ₂ alkoxy, C ₃ -C ₅ cycloalkoxy, C3-C5 cycloalkylmethoxy, either completely or predominantly fluoro-substituted C ₁ -C ₂ alkoxy,

KZ stands for hydrogen atom,

KZ 1 denotes a hydrogen atom,

K4 is a hydrogen atom or C ₁ C2 alkyl,

K5 represents a hydrogen atom,

K51 represents a hydrogen atom or in which

K5 and K51 together denote an additional bond,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10, 8 (O) ₂ -aryl, O-8 (O) ₂ -K11, pyrrolidin-1-yl, pyrrolidin-1-yl -2-one or pyrrolidin-1-yl2,5-dione, where

K7 is C ₃ -C ₇ cycloalkyl, C ₃ C ₇ cycloalkylmethyl, C ₁ -C ₄ alkoxy-C ₄ -C ₄ alkyl, aryl or phenyl-C ₁ -C ₄ alkyl,

K8 represents a hydrogen atom, C ₁ C4 alkyl, acetyl, phenylcarbonyl, trifluoromethyl or phenyl,

K9 is C 1 -C ₄ alkyl, C ₃ C ₇ cycloalkyl, C ₃ -C 7 cycloalkylmethyl, 1 piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl,

K10 is a halogen atom, carboxyl, _C1-C4 alkoxy, phenoxy, C ₄ -C ₄ alkoxycarbonyl, aminocarbonyl, mono- or di-C ₁ C ₄ alkylaminocarbonyl, Ν (Κ15) Κ16 or C _p S4alkilkarbonilaminogruppu and

K11 is _C1-C4 alkyl, mono-or diS1 S4alkilaminogruppu or aryl, aryl is phenyl, pyridyl or phenyl K12zameschenny where

K12 represents a halogen atom, a carboxyl, nitro, amino, cyano group, C1-C4 alkyl, trifluoromethyl or C1-C4 alkoxy,

K13 is hydrogen, hydro xylitol, halogen, cyano, nitro, aminogrup ny, _C1-C4 alkyl, trifluoromethyl, C ₄ -C ₄ alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, phenyl, phenyl-C1-C4alkyl , C (O) OK14, C (O) -Y (K15) K16, Ν (Κ17) Κ18, 8 (O) ₂ -K19, 8 (Ό) ₂ -Ν (Κ15) Κ16, or has one of the values of K6, Where

K14 represents a hydrogen atom or C1C4 alkyl,

K15 represents a hydrogen atom or C1C4 alkyl,

K16 represents a hydrogen atom, C1C4 alkyl or aryl, or when

K15 and K16, together and including the nitrogen atom to which they are attached, represent a 1 piperidyl, 1-piperazinyl, 1-methylpiperazin-4-yl or 4-morpholinyl radical,

K17 is hydrogen, C1C ₄ alkyl, 8 (O) -K19 ₂ or 8 (O) ₂ -aryl,

K18 is _C1-C4 alkyl, _{C1-C4-alkylcarbonyl,} C3-S7tsikloalkilkarbonil, S3S tsikloalkilmetilkarbonil _7, 8 (OH) ₂ or -K19

8 (O) ₂ -aryl, and

K19 is _C1-C4 alkyl,

K20 denotes a hydrogen atom, hydroxyl, halogen atom, nitro, amino group, C ₁ C ₄ alkyl, trifluoromethyl, C ₄ -C ₄ alkoxy, fully or predominantly fluoro-substituted C ₁ -C ₄ alkoxy, C ₃ -C ₇ cycloalkoxy, C ₃ -C ₇ cycloalkylmethoxy, carboxyl, C 1 -C C ₄ alkoxycarbonyl or C1-C4 alkylcarbonyloxy, as well as salts, Ν-oxides and salts of идов-oxides of these compounds.

Among the compounds of formula I in option A, those in which

R1 is _{C1-C2-alkoxy,}

R2 is _{C1-C2-alkoxy,}

K3, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10, 8 (O) _2- phenyl, O-8 (O) ₂ -K11, pyrrolidin-1yl, pyrrolidin-1-yl-2 -one or pyrrolidin-1yl-2,5-dione, where

K7 is C ₃ -C ₅ cycloalkyl, C ₃ C5 cycloalkylmethyl, C1-C2 alkoxy-C1-C2 alkyl, aryl or phenyl-C1-C2 alkyl,

K8 is phenyl,

R9 is _C1-C4 alkyl, _C3-C5 cycloalkylmethyl, 1-piperidinyl or aryl,

K10 denotes a halogen atom, C ₄ C ₄ alkoxycarbonyl or Ν (Κ15) ,16, and

K11 is methyl or 4-methylphenyl; aryl is phenyl, pyridyl or

K12-substituted phenyl, where K12 is a _C1-C4 alkyl, _C1-C4 alkoxy, halogen, nitro or cyano,

K15 is _C1-C4 alkyl, and

K16 is _C1-C4 alkyl, or

K15 and K16, together and including the nitrogen atom to which they are bonded, represent a 1 piperidinyl, 1-piperazinyl, 19 methylpiperazin-4-yl or 4-morpholinyl radical, and in which either

K13 denotes a hydrogen atom, C | C ₄ alkoxy, fully or predominantly fluoro-substituted C ₁ -C ₂ alkoxy, C ₁ -C ₄ alkylcarbonylamino group, and

K20 is a hydrogen atom, or K13 is a hydrogen atom, and K20 is C ₃ -C ₅ cycloalkoxy or C ₃ -C ₅ cycloalkylmethoxy, as well as salts, также-oxides and salts of Ν-oxides of these compounds.

Among the compounds of formula I for option A, those in which

K1 is C ₁ -C ₂ alkoxy,

K2 is C ₁ -C ₂ alkoxy,

KZ, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is O-K7, 8-K8, C (O) -K9, SSCK10, 8 (O) _2- phenyl, O-8 (O) ₂ -K11, pyrrolidin-1yl or pyrrolidin-1-yl-2-one where

K7 is cyclobutyl, cyclopentyl, cyclopropylmethyl, 2-methoxyethyl, phenyl, 4methoxyphenyl, benzyl, phenethyl or pyridyl,

K8 is phenyl,

K9 is methyl, ethyl, isobutyl, cyclopropylmethyl, 1-piperidinyl or aryl,

K10 is methoxycarbonyl, morpholin-4-yl or 1-methylpiperazin-4-yl, and

K11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or K12 substituted phenyl, where

K12 is methoxy, a halogen atom, a nitro or cyano group, and in which either K13 is a hydrogen atom, methoxy, ethoxy, difluoromethoxy or acetylamino, and K20 is a hydrogen atom, or

K13 is a hydrogen atom, and K20 is cyclopropylmethoxy, as well as salts, β-oxides and salts of β-oxides of these compounds.

In another embodiment (Embodiment B) of the invention, there are provided compounds of formula I in which

R1 represents hydroxyl, _C1-C4 alkoxy, C3-S7tsikloalkoksi, C3-S7tsikloalkilmetoksi or completely or predominantly fluorine-substituted C ₁ -C ₄ alkoxy,

R2 is hydroxy, C1-C ₄ alkoxy, C ₃ -C ₇ cycloalkoxy, C ₃ -C ₇ cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-C4 alkoxy, or in which

K1 and K2 together denote a C1C2 alkylenedioxy group,

K3 is a hydrogen atom or C1C4 alkyl,

K31 denotes a hydrogen atom or C1C ₄ alkyl, or in which

K3 and K31 together represent a C ₁ C ₄ alkylene group,

K4 is a hydrogen atom or C1C4 alkyl,

K5 represents a hydrogen atom,

K51 denotes a hydrogen atom, or in which

K5 and K51 together denote an additional bond,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10 or O-8 (O) ₂ -K11, where

K7 is C3-C7 cycloalkyl, C3C7 cycloalkylmethyl, aryl or phenyl-C1C4 alkyl,

R8 represents a hydrogen atom, C1C ₄ alkyl, C1C ₄ alkylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl,

R9 is _C1-C4 alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4metilpiperazinil, 4-morpholinyl or aryl,

K10 is hydroxyl, halogen, cyano, carboxyl, C1-C4 alkoxy, phenoxy, C 1 -C 4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-S4alkilaminokarbonil, K15 ^) K16 or _C1-C4 alkylcarbonylamino, and

K11 is C1-C4 alkyl, amino, mono or di-C ₁ -C ₄ alkylamino or aryl, aryl is phenyl, pyridyl or K12 substituted phenyl, where

K12 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, C ₁ -C 4 alkyl, trifluoromethyl, C1-C4alkoxy, S1S4alkoksikarbonil, C1-S4alkilkarbonilaminogruppu, C1-S4alkilkarboniloksi or aminocarbonyl,

K13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-C4alkyl, trifluoromethyl, C1-C4 alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, phenyl, phenyl-C1C ₄ alkyl, C (O) OK14, С (О) ^ (К15) К16, ^ К17) К18, 8 (О) ₂ -К19, 8 (О) ₂ -Л (К15) К16 or has one of the values К6, where

K14 represents a hydrogen atom, C1-4 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylmethyl,

K15 is a hydrogen atom, C1C4 alkyl, C3-C7 cycloalkyl or C3C7 cycloalkylmethyl,

K16 is a hydrogen atom, C1-4 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylmethyl or aryl, or when

K15 and K16 together and including the nitrogen atom to which they are bonded, represent 1 pyrrolidinyl, 1-piperidinyl, 1 piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical,

K17 represents a hydrogen atom, C1C4 alkyl, 8 (O) 2-K19 or 8 (O) 2-aryl,

K18 is C1-C4 alkyl, C1-C4 alkylcarbonyl, 8 (O) 2-K19 or 8 (O) 2-aryl, and

K19 is C1-C4 alkyl,

K20 denotes a hydrogen atom, hydroxyl, a halogen atom, a nitro, amino group, C ₁

C ₄ alkyl, trifluoromethyl, C1-C ₄ alkoxy, fully or predominantly fluorine-substituted C ₁ -C ₄ alkoxy, C ₃ -C ₇ cycloalkoxy, C ₃ -C ₇ cycloalkylmethoxy, CH ₂ -K10, carboxyl, C ₁ C ₄ alkoxycarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₁ -C ₄ alkylcarbonylamino group or aminocarbonyl, as well as salts, окс-oxides and salts of Ν-oxides of these compounds.

Among the compounds of formula I in embodiment B, those in which

K.1 is C ₁ -C ₂ alkoxy, C ₃ -C ₅ cycloalkoxy, C ₃ -C ₅ cycloalkylmethoxy, either completely or predominantly fluoro-substituted C ₁ -C ₂ alkoxy,

K2 is C ₁ -C ₂ alkoxy, C ₃ C ₅ cycloalkoxy, C ₃ -C ₅ cycloalkylmethoxy, either completely or predominantly fluoro-substituted C ₁ -C ₂ alkoxy,

K3 represents a hydrogen atom,

KZ 1 denotes a hydrogen atom,

K4 is a hydrogen atom or C ₁ C2 alkyl,

K5 represents a hydrogen atom,

K51 denotes a hydrogen atom, or in which

K5 and K51 together denote an additional bond,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10 or O-8 (O) ₂ -K11, where

K7 is C3-C7 cycloalkyl, C3C7 cycloalkylmethyl, aryl or phenyl-C1C4 alkyl,

K8 represents a hydrogen atom, C1-4 alkyl, acetyl, trifluoromethyl or phenyl,

K9 is C ₁ -C ₄ alkyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4morpholinyl or aryl,

K10 denotes a halogen atom, carboxyl, C ₁ -C ₄ alkoxy, phenoxy, C ₁ -C ₄ alkoxycarbonyl, aminocarbonyl, mono- or di-C1-C4 alkylaminocarbonyl, Ν (Κ15) Κ16 or C ₁ -C ₄ alkylcarbonylamino group, and

K11 is a C1-C4 alkyl, mono- or diC1-C2 alkylamino group or aryl, aryl is phenyl, pyridyl or K12-substituted phenyl, where

K12 represents a halogen atom, a carboxyl, nitro, amino, cyano group, C ₁ -C ₄ alkyl, trifluoromethyl or C ₁ -C ₄ alkoxy,

K13 denotes a hydrogen atom, hydroxyl, a halogen atom, a cyano, nitro, amino group, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₄ alkoxy, fully or predominantly fluoro-substituted C ₁ -C ₄ alkoxy, phenyl, phenyl-C 1C ₄ alkyl, C (O) OK14, C (O) -L (K15) K16,

Ν (Κ17) Κ18, 8 (О) ₂ -К19, 8 (О) ₂ -Л (К15) К16 or has one of the values of К6, where

K14 represents a hydrogen atom or C1C4 alkyl,

K15 represents a hydrogen atom or C1C4 alkyl,

K16 represents a hydrogen atom, C1C4 alkyl or aryl, or when

K15 and K16, together and including the nitrogen atom to which they are attached, denote a 1 piperidyl, 1-piperazinyl, 4 methylpiperazin-1-yl or 4-morpholinyl radical,

K17 is hydrogen, C1C ₄ alkyl, 8 (O) -K19 ₂ or 8 (O) ₂ -aryl,

K18 is C1-C4 alkyl, C1-C4 alkylcarbonyl, 8 (O) ₂ -K19 or 8 (O) ₂ -aryl, and

K19 is _C1-C4 alkyl,

K20 is hydrogen, hydroxyl, halogen, nitro, amino, C1C ₄ alkyl, trifluoromethyl, C _£ -C ₄ alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, C3-S7tsikloalkoksi, S3S7tsikloalkilmetoksi, carboxyl, C1C ₄ alkoxycarbonyl or C 1 -C C ₄ alkylcarbonyloxy, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds.

Among the compounds of formula I in embodiment B, those in which

K1 is C ₁ -C ₂ alkoxy,

K2 is C ₁ -C ₂ alkoxy,

KZ, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10 or O-8 (O) ₂ -K11, where

K7 is C3-C7 cycloalkyl, C3C5 cycloalkylmethyl, phenyl or phenyl-C1C2 alkyl,

K8 is phenyl,

K9 is methyl, 1-piperidinyl or phenyl,

K10 represents a halogen atom, C | C ₄ alkoxycarbonyl or MK15) K16. but

K11 is methyl or 4-methylphenyl,

K15 is _C1-C4 alkyl, and

K16 is _C1-C4 alkyl, or wherein

K15 and K16, together and including the nitrogen atom to which they are bonded, are 1 piperidinyl, 1-piperazinyl, 1 methylpiperazin-4-yl or 4-morpholinyl radical, and in which either K13 is a hydrogen atom, methoxy or ethoxy, and K20 is a hydrogen atom or K13 is a hydrogen atom, and K20 is C3-C5 cycloalkoxy or C3C ₅ cycloalkylmethoxy, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds.

In Embodiment B, preferred compounds of formula I are those in which

R1 is _{C1-C2-alkoxy,}

R2 is _{C1-C2-alkoxy,}

K3, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is O-K7, 8-K8, C (O) -K9, CH2K10 or O-8 (O) ₂ -K11, where

K7 is cyclopentyl, cyclopropylmethyl, phenyl, benzyl or phenethyl,

K8 is phenyl,

K9 is methyl, 1-piperidinyl or phenyl,

K10 represents a halogen atom, methoxycarbonyl, morpholin-4-yl or 1-methylpiperazin-4-yl, and

K11 is methyl or 4-methylphenyl, and in which either K13 is a hydrogen atom or methoxy, K20 is a hydrogen atom, or K13 is a hydrogen atom, and K20 is cyclopropylmethoxy, as well as salts, окс-oxides and salts of Ν-oxides of these compounds .

In yet another embodiment (Embodiment B) of the invention, there are provided compounds of formula I in which

R1 is _C1-C2 alkoxy, C ₃ C ₅ cycloalkoxy, C ₃ -C ₅ cycloalkylmethoxy or completely or predominantly fluorine-substituted C1-S2alkoksi,

K2 is C _g C ₂ alkoxy, C ₃ C5 cycloalkoxy, C3-C5 cycloalkylmethoxy, either completely or predominantly fluoro-substituted C ₁ -C ₂ alkoxy,

K3 represents a hydrogen atom,

KZ 1 denotes a hydrogen atom,

K4 is a hydrogen atom or C1C2 alkyl,

K5 represents a hydrogen atom,

K51 denotes a hydrogen atom, or in which

K5 and K51 together denote an additional bond,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10, 8 (O) _2- phenyl or O-8 (O) ₂ -K11, where

C7 denotes a C ₃ -C ₅ cycloalkyl, C _{3 to} C ₅ cycloalkylmethyl, C 1 -C ₂ alkoxy-C 1 -C ₂ alkyl, aryl or _{phenyl-C1-C2-alkyl,}

K8 is phenyl,

R9 is C1-C ₄ alkyl, C ₃ -C ₅ cycloalkylmethyl, 1-piperidinyl or aryl,

K10 represents a halogen atom, and

K11 is _C1-C4 alkyl or aryl, aryl is phenyl or K12-substituted phenyl, wherein

K12 is a halogen atom, a nitro group, a _C1-C4 alkyl or _C1-C4 alkoxy,

K13 is hydrogen, C1C ₄ alkoxy, C1C ₄ alkyl carbonylamino or completely or predominantly fluorine-substituted C1-S2alkoksi and

K20 denotes a hydrogen atom, C ₃ C ₅ cycloalkoxy or C ₃ -C 5 cycloalkylmethoxy, as well as salts, β-oxides and salts of β-oxides of these compounds.

Among the compounds of formula I according to embodiment B, those in which

K1 is C ₁ -C ₂ alkoxy,

K2 is C ₁ -C ₂ alkoxy,

K3, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10, 8 (O) _2- phenyl or O-8 (O) ₂ -K11, where

C7 denotes a C ₃ -C ₅ cycloalkyl, C _{3 to} C ₅ cycloalkylmethyl, C 1 -C ₂ alkoxy-C 1 -C ₂ alkyl, aryl or _{phenyl-C1-C2-alkyl,}

K8 is phenyl,

R9 is C1-C ₄ alkyl, C ₃ S5tsikloalkilmetil, 1-piperidinyl or aryl,

K10 represents a halogen atom, and

K11 is _C1-C4 alkyl or aryl, aryl is phenyl or K12-substituted phenyl, wherein

K12 is a halogen atom, a nitro group, a _C1-C4 alkyl or _C1-C4 alkoxy,

K13 is hydrogen, C ₁ -C 4 alkoxy, C 1 S4alkilkarbonilaminogruppu or completely or predominantly fluorine-substituted C1-S2alkoksi and

K20 denotes a hydrogen atom, C ₃ C ₅ cycloalkoxy or C ₃ -C 5 cycloalkylmethoxy, as well as salts, β-oxides and salts of β-oxides of these compounds.

In Embodiment B, preferred compounds of formula I are those in which

K1 is C ₁ -C ₂ alkoxy,

K2 is C ₁ -C ₂ alkoxy,

K3, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is acetyl, ethylcarbonyl, isobutylcarbonyl, cyclopropylmethylcarbonyl, benzoyl, 4-methoxyphenylcarbonyl, 4-chlorophenylcarbonyl, 3-chlorophenylcarbonyl, 4nitrophenylcarbonyl, thiophenoxy, phenoxy, 4methoxyphenyloxyphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenyl 1-ylcarbonyl,

K13 represents a hydrogen atom and

K20 denotes a hydrogen atom, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds.

Other preferred option B compounds of formula I are those in which

R1 is _{C1-C2-alkoxy,} R2 is C ₁ -C ₂ alkoxy,

K3, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is benzyloxy, methoxyethoxy, cyclopropylmethoxy or cyclobutoxy, and in which either K13 is a methoxy, ethoxy or acetylamino group, K20 is a hydrogen atom, or K13 is a hydrogen atom, and K20 is cyclopropylmethoxy, as well as salts, Ν-oxides and Ν- salts oxides of these compounds.

Particularly preferred in embodiment B, compounds of formula I are those in which

K1 is methoxy,

K2 is methoxy or ethoxy,

KZ, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is acetyl, benzoyl, phenoxy or piperid-1-ylcarbonyl,

K13 represents a hydrogen atom and

K20 denotes a hydrogen atom, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds.

Other particularly preferred compounds B of formula I are those in which

K1 is methoxy,

K2 is methoxy or ethoxy,

K3, K31, K4, K5 and K51 denote hydrogen atoms,

K6 is cyclopropylmethoxy or cyclobutoxy, and in which either K13 is methoxy or ethoxy, and K20 is a hydrogen atom, or

K13 is a hydrogen atom, and K20 is cyclopropylmethoxy, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds.

Compounds of formula I are chiral compounds which have chiral centers at positions 4a and 10b and, depending on substituents K3, K31, K4, K5 and K51, additional chiral centers at positions 1, 2, 3 and 4.

Numbering of provisions:

Thus, the scope of the invention covers all possible pure diastereoisomers and pure enantiomers, as well as mixtures thereof in any ratios of miscible substances, including racemates. Preferred are compounds of formula I in which the positions 4a and 10b of the hydrogen atoms with respect to each other correspond to the cis configuration. Pure cis enantiomers are especially preferred.

In this regard, those compounds of formula I in which the positions 4a and 10b correspond to the same absolute configuration as the compound (-) cis-1,2-dimethoxy-4- (2-aminocyclohexyl) benzene, which may be used as the starting compound and is characterized by optical rotation [α] _Β ²⁰ = -58.5 ° (c = 1, ethanol).

Enantiomers can be resolved according to a method that is known (for example, by preparation and isolation of the corresponding diastereoisomeric compounds). In a preferred embodiment, the isolation of the enantiomer is carried out at the stage of the starting compounds of formula IV

for example, by preparing salts of racemic compounds of formula IV of optically active carboxylic acids. Examples that may be mentioned in connection with this are enantiomeric forms of mandelic acid, tartaric acid, O, O'-dibenzoyl tartaric acid, camphoric acid, quinic acid, glutamic acid, malic acid, camphorsulfonic acid, 3-bromocamphorsulfonic acid, α- methoxyphenylacetic acid, α-methoxy-a-trifluoromethylphenylacetic acid and 2-phenylpropionic acid. In another embodiment, enantiomerically pure starting materials of formula IV may be prepared by asymmetric synthesis.

The process of obtaining compounds of formula I, in which K1, K2, K3, K31, K4, K5, K51, K6, K13 and K20 have the meanings indicated above, and their salts can be carried out, for example, by the method that is described in more detail below.

This method involves cyclocondensation of compounds of formula II

in which K1, K2, K3, K31, K4, K5, K51, K6, K13 and K20 have the meanings indicated above, and optional subsequent conversion of the obtained compounds of formula I to their salts or optional subsequent conversion of the obtained salts of the compounds of formula I to free compounds .

The resulting compounds of formula I by derivatization can (optionally) be converted to other compounds of formula I.

So, for example, from compounds of formula I, in which

a) K12 and / or K13 and / or K20 represents an ester group, the corresponding acids can be obtained by acid or basic hydrolysis, or the corresponding amides can be obtained by reaction with appropriately substituted amines;

b) K12 and / or K20 represents a C1C4 alkylcarbonyloxy group, the corresponding hydroxyl compounds can be obtained by acid or basic hydrolysis;

c) one or more radicals K10, K12, K13 and K20 denote nitro groups corresponding to amino compounds, which, in turn, can be subjected to further derivatization, can be obtained by selective catalytic hydrogenation.

The methods described in sections a), b) and c) are suitably carried out analogously to methods known to those skilled in the art.

In addition, compounds of formula I can be (optionally) converted to their oxides, for example, using hydrogen peroxide in methanol or using chloroperoxybenzoic acid in dichloromethane. If we take into account the knowledge that a person skilled in the art possesses, then he knows the specific conditions that must be created when carrying out the oxidation reaction.

Cyclocondensation is carried out in a way that is known to a person skilled in the art, in accordance with the Bischler-Napiralsky method (for example, as set forth in TSIet.8os., 1956, 4280-4282), in the presence of an acceptable condensation agent, such as for example polyphosphoric acid phosphorus pentachloride, phosphorus pentoxide or, preferably, phosphorus oxychloride, in a suitable inert solvent, in particular in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene and xylene, or other inert m a solvent such as acetonitrile, or without solvent, using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.

The compounds of formula II, in which K1, K2, KZ, K31, K4, K5, K51, K6, K13 and K20 have the meanings indicated above, can be obtained from the corresponding compounds of formula IV, in which K1, K2, KZ, K31, K4, K5 and K51 are as defined above by reaction with compounds of formula III

L ^(|||) r f — Kb

K20 _K13 in which K6, K13 and K20 have the meanings indicated above, and X represents the corresponding leaving group, preferably a chlorine atom. So, for example, acylation or benzoylation is carried out as described in the following examples or in EU 8oc. (C), 1971, 18051808.

Compounds of formula III and compounds of formula IV are either known or may be prepared in a known manner.

Compounds of formula IV can be prepared, for example, from compounds of formula V K4 · _W? ⁵

KZ .. > C, K4 | pK51 K2 _X 'UKZ1 KG -M ΝΟ ₂ (V)

in which K1, K2, K3, K31, K4, K5 and K51 have the meanings indicated above, by reduction of the nitro group.

This recovery is carried out in a way that is known to the person skilled in the art, for example, as set forth in Sec. 1962, 27, 4426 or as set forth in the following examples.

The reduction can be carried out, for example, by catalytic hydrogenation, in particular in the presence of Raney nickel, in a lower alcohol such as methanol or ethanol, at room temperature and under normal or elevated pressure. A catalytically effective amount of an acid, such as, for example, hydrochloric acid, can be added to the solvent (but not necessarily). However, in a preferred embodiment, the reduction is carried out using metals such as zinc and iron, together with organic acids, such as acetic acid, or mineral acids, such as hydrochloric acid.

Compounds of formula IV in which K1, K2, K3, K31 and K4 are as defined above, and K5 and K51 together represent an additional bond, can be obtained from the corresponding compounds of formula V by selective reduction of the nitro group in a manner that is skilled in the art It is known, for example, in the presence of Raney nickel in lower alcohol as a solvent using hydrosine hydrate as a hydrogen donor.

Compounds of formula V in which K1, K2, K3, K31 and K4 have the meanings given above, and K5 and K51 are hydrogen atoms, are either known or can be obtained from the corresponding compounds of formula V, in which K5 and K51 together represent an additional communication. The reaction can be carried out in a manner that is known to a person skilled in the art, preferably by hydrogenation in the presence of a catalyst, such as, for example, palladium on activated carbon, in particular as set forth in TC11et. (C), 1971, 1805-1808.

Compounds of formula V in which K5 and K51 together represent an additional bond are either known or may be prepared by the reaction of compounds of formula VI

in which K1 and K2 have the meanings indicated above, with compounds of formula VII

K3-CH = C (K4) -C (K4) = CH-K31 (VII), in which KZ, KZ 1 and K4 have the meanings indicated above.

Compounds of formula V, in which K5 and K51 together represent an additional bond, and KZ and K31 together represent a C ₁ C ₄ alkylene group, can be obtained, for example, by the reaction of cyclic compounds of formula VII, in which K4 has the meanings given above, and K3 and K31 together represent a C1-C4 alkylene group (e.g., cyclohexa-1,3-diene, 2,3-dimethylcyclohexa-1,3-diene, cyclohepta-1,3-diene, 2,3-dimethylcyclohepta 1,3-diene or cycloocta -1,3-diene), with compounds of formula VI, in which K1 and K2 have the above meanings.

In this case, cycloaddition is carried out in such a way as is known to a person skilled in the art in accordance with the Diels-Alder method, for example, as described in 1. Asheg. 1957, 79, 6559 or Utd. C1esh. 1952, 17, 581, or as set forth in the following examples.

Compounds of the formula V obtained by cycloaddition, in which the phenyl ring and nitro group are trans-relative to each other, can be converted in a manner known to the person skilled in the art into the corresponding cis compounds, for example, as described in 1 .Asheg.Syesh.8os. 1957, 79, 6559 or as set forth in the following examples.

The compounds of formulas VI and VII are either known or can be obtained in a known manner. Compounds of formula VI can be prepared, for example, by a method known to a person skilled in the art, from the corresponding compounds of formula VIII, as set forth, for example, in 1C. 1951, 2524 or Utd.Syesh. 1944, 9, 170, or as set forth in the following examples.

Compounds of Formula VIII

in which K1 and K2 have the meanings indicated above, are either known or can be obtained in a way that is known to a person skilled in the art, as described, for example, in Veg.P18s.Syesh.Se8. 1925, 58, 203.

In addition, one of ordinary skill in the art will recognize that if a parent or intermediate has a certain number of reactive sites, it may be necessary to temporarily block one or more reactive sites with protective groups so that a specific reaction can take place at the site of the target reactive site. A detailed description of the use of a large number of tested protective groups is contained, for example, in T. ^. Sgiep, PtolecNue Sgoyrk ίη Ogdashs ZuySheyk, 1o1sh \ UPeu & 8op5.

1991.

The isolation and purification of substances in accordance with the invention is carried out in a manner that is known, for example, by distilling off the solvent under vacuum and recrystallizing the resulting residue from an acceptable solvent or by treating it according to one of the usual purification methods, in particular, column chromatography on a suitable support material.

Salts are prepared by dissolving the free compound in an acceptable solvent (for example, a ketone such as acetone, methyl ethyl ketone and methyl isobutyl ketone, in a simple ether such as diethyl ether, tetrahydrofuran and dioxane, in a chlorinated hydrocarbon such as methylene chloride and chloroform, or in a low molecular weight aliphatic aliphatic such as ethanol and isopropanol), which includes the target acid or base, or to which the target acid or base is further added. Salts are obtained by filtration, reprecipitation, non-solvent precipitation in the case of an addition salt or evaporation of the solvent. By alkalizing or acidifying, the salts obtained can be converted into free compounds, which, in turn, can be converted into salts. In this way, pharmacologically unacceptable salts can be converted to pharmacologically acceptable salts.

The following examples serve to further illustrate the invention without limiting its scope. In a similar manner or in a manner that is well known to a person skilled in the art, using the known technology, other compounds of the formula I can be obtained, the preparation of which is not explicitly described.

In these examples, the abbreviation 1 _PL indicates the melting point, h means hour (hours), CT means room temperature, EF means the empirical formula, M \ m is the molecular weight, calc. means calculated, detected. means detected. The compounds mentioned in the examples and their salts are preferred objects of the invention.

Examples

End products.

1. (-) - cis-8,9-Dimethoxy-6- (4-benzoylphenyl) -1,2,3,4,4a, 10b-hexahydrophenanthridine.

7.1 g of (-) - cis-Y- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-benzoylbenzamide (compound A1) was dissolved in 100 ml of acetonitrile and 5.0 ml of phosphoryl chloride and stirred overnight at 80 ° C. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate and ethyl acetate. After chromatography on silica gel using petroleum 21 ether (low boiling fraction) / ethyl acetate / triethylamine (6/3/1) and concentration of the product containing fractions, 5.3 g of the title compound are obtained.

EF: 0 ₂₈ Η ₂₇ Ν0 ₃ ; Mm: 425.53

Elemental analysis (x 0.08 H ₂ O): calc .: C 78.77; H 6.41; Ν 3.28 found: C 78.55; H 6.64; Ν 3.50

Optical rotation: | α | _υ ²⁰ = -70.6 ° (c = 0.2, ethanol)

Analogously to example 1 using the following compounds as starting materials, the following is obtained.

2. (-) - cis-8,9-Dimethoxy-6- (4-acetophenyl) 1,2,3,4,4a, 10b-hexahydrophenanthridine.

EF: C ₂₃ H ^ O ₃ ; Mm: 363,46

Elemental analysis:

calc .: C 76.01; H 6.93; Ν 3.85 found: C 75.77; H 6.98; Ν 3.82

Optical rotation: [a] _s ²⁰ = -97.4 ° (s = 0.2, ethanol)

3. (-) - cis-8,9-Dimethoxy-6- (3-benzoylphenyl) -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: C ₂₈ H ₂ ^ O ₃ ; Mm: 425.53

Elemental analysis (x 0.15 H2O): calc .: C 78.54; H 6.43; Ν 3.27 found: C 78.39; H 6.58; Ν 3.40

Optical rotation: [AC ²⁰ = -96.8 ° (c = 0.2, ethanol)

4. (-) - cis-8,9-Dimethoxy-6- (4-phenoxyphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: Ο ₂₇ Η ₂₇ ΝΘ ₃ ; Mm: 413.52; 1 _pl : 110-115 ° C

Elemental analysis:

calc .: C 78.42; H 6.58; Ν 3.39 found: C 78.44; H 6.61; Ν 3.29

Optical rotation: [a] _c ²⁰ = -63 ° (c = 0.2, ethanol)

5. (-) - cis-8,9-Dimethoxy-6- (3-phenoxyphenyl) -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: Ο ₂₇ Η ₂₇ ΝΘ ₃ ; Mm: 413.52

Elemental analysis: (x 0.23 H ₂ O): calc .: C 77.64; H 6.63; Ν 3.35 found: C 77.77; H 6.71; Ν 3.22

Optical rotation: [α] _ο ²⁰ = -46.4 ° (c = 0.2, ethanol)

6. (-) - cis-8,9-Dimethoxy-6- [3- (phenylthio) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: 0 ₂₇ Η ₂₇ Ν0 ₂ 8; MM: 429.59

Elemental analysis (x 0.32 H ₂ O): calc .: C 74.48; H 6.40; Ν 3.22; 8 7.36 detection: C 74.82; H 6.44; Ν

3.22; 8 7.02

Optical rotation: [α] _ο ²⁰ = -66 ° (c = 0.2, ethanol)

7. (-) - cis-8,9-Dimethoxy-6- (3-benzyloxyphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: 0 ₂₈ Η ₂₈ Ν 0 ₃ ; Mm: 427.55; 1 _pl : 118-120 ° C

Elemental analysis:

calc .: C 78.66; H 6.83; Ν 3.28 found: C 78.62; H 6.90; Ν 3.26

Optical rotation: [α] _ο ²⁰ = -79.2 ° (c = 0.2, ethanol)

8. (-) - cis-8,9-Dimethoxy-6- (3-phenyloxyphenyl) -1,2,3,4,4a, 10b-hexahydrophenanthridine.

EF: C ₂₉ H ₃ ^ O ₃ ; Mm: 441.58

Elemental analysis (x 0.2 N ₂ O): calc .: C 78.24; H 7.11; Ν 3.15 found: C 78.29; H 7.26; Ν 3.03

Optical rotation: [a] _s ²⁰ = -73.6 ° (s = 0.2, ethanol)

9. (-) - cis-6- (3-Cyclopentyloxy-4-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 10-hexahydrophenanthridine

EF: 0 ₂₇ Η ₃₃ Ν0 ₄ ; Mm: 435.57

Elemental analysis (x 0.2 Η ₂ 0): calc .: C 73.84; H 7.67; Ν 3.19 found: C 73.59; H 7.86; Ν 3.48

Optical rotation: [α] _ο ²⁰ = -78.5 ° (c = 0.2, ethanol)

10. (-) - cis-6- (4-Benzyloxy-3-cyclopropylmethoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 10H-hexahydrophenanthridine.

EF: 0 ₃₂ Η ₃₅ Ν0 ₄ ; MM: 497.64

Elemental analysis (x 0.27 H2O): calc .: C 76.50; H 7.13; Ν 2.79 found: C 76.44; H 7.12; Ν 2.85

Optical rotation: [α] _ο ²⁰ = -72.2 ° (c = 0.2, ethanol)

11. (+) - cis-6- (3-Benzyloxy-4-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 10b-hexahydrophenanthridine.

EF: 0 ₂₉ Η ₃₁ Ν0 ₄ ; Mm: 457.57

Elemental analysis (x 0.22 H ₂ O): calc .: C 75.46; H 6.87; Ν 3.03 detection: C 75.57; H 6.96; Ν 2.92

Optical rotation: [a] _s ²⁰ = + 83.8 ° (s = 0.2, ethanol)

12. (-) - cis-8,9-Dimethoxy-6- (3-cyclopropylmethoxy-4-methoxyphenyl) -1,2,3,4,4a, 10H-hexahydrophenanthridine.

EF: 0 ₂₆ Η ₃₁ Ν0 ₄ ; MM: 421.54

Elemental analysis:

calc .: C 74.08; H 7.41; Ν 3.32 found: C 73.84; H 7.54; Ν 3.44

Optical rotation: [α] _ο ²⁰ = -92.2 ° (c = 0.2, ethanol)

13. (-) - cis-8,9-Dimethoxy-6- (3-methanesulfonyloxyphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: 0 ₂₂ Η ₂ 5Ν0 ₅ 8; Mm: 415.51

Elemental analysis (x 0.35 H20): calc .: C 62.63; H, 6.14; Ν 3.32 found: C, 62.97; H, 6.26; Ν 3.14

Optical rotation: [a] _s ²⁰ = -82.6 ° (s = 0.2, ethanol)

14. (-) - cis-8,9-Dimethoxy-6- [3- (p-toluenesulfonyloxy) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: SyGSHYuZZ; Mm: 491.61

Elemental analysis (x 0.45 H ₂ O): calc .: C 67.30; H 6.03; Ν 2.80; 8 6.42 found .: C 67.52; H 6.03; N, 2.58; 8 6.20

Optical rotation: [α] _ο ²⁰ = -52.2 ° (c = 0.2, ethanol)

15. (-) - cis-8,9-Dimethoxy-6- [3,4-bis (diclopropylmethoxy) phenyl] -1,2,3,4,4a, 10H hexahydrophenanthridine.

EF: Ο ₂₉ Η ₃₅ ΝΘ ₄ ; Mi: 461.61

Elemental analysis (x 0.13 H ₂ O): calc .: C 75.08; H, 7.66; N, 3.02; found: C, 74.90; H 7.64; N 3.21

Optical rotation: [α] _ο ²⁰ = -80 ° (c = 0.2, ethanol)

16. (-) - cis-8,9-Dimethoxy [4- (piperidin-1-carbonyl) phenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: Ο ₂₇ Η ₃₂ Ν ₂ Θ ₃ ; Mi: 432.57

Elemental analysis:

calc .: C 75.95; H 7.53; N, 6.09; found: C, 75.80; H 7.55; N 5.79

Optical rotation: [a] _s ²⁰ = -57.6 ° (s = 0.2, ethanol)

17. (-) - cis-8,9-Dimethoxy [3- (piperidin-1-carbonyl) phenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: C ₂₇ H ₃₂ ^ O ₃ ; Mi: 432.57; I: 182-185 ° C

Elemental analysis:

calc .: C 75.95; H 7.53; N, 6.09; found: C, 75.19; H 7.49; N, 6.28

Optical rotation: [α] _ο ²⁰ = -83.6 ° (c = 0.2, ethanol)

18. (-) - cis-8,9-Dimethoxy-6- (4-methoxycarbonylmethylphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₄ H ₂ ^ O ₂ ; Mi: 393.49; V 124-125 ° C

Elemental analysis:

calc .: C, 73.26; H 6.92; N, 3.56 found: C, 73.34; H 6.94; N 3,55

Optical rotation: [α] _ο ²⁰ = -91 ° (c = 0.2, ethanol)

19. cis-6- (4-chloromethylphenyl) -9-ethoxy-8methoxy-1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C2 ₃ N26SShO2; Mi: 383.92; V 151153 ° C

Elemental analysis (x 0.25 N ₂ O):

calc .: C, 71.09; H 6.88; N, 3.60; C1, 9.12 found: C, 71.63; H 6.87; N, 3.50; C1 8.57

20. (-) - cis-6- (4-chloromethylphenyl) -8,9dimethoxy-1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₂ H ₂₄ SCO ₂ ; Mi: 369.9

YAG = 0.6 (neutral silica gel, toluene / dioxane, 2/1)

Optical rotation: [α] _ο ²⁰ = -247.3 ° (c = 0.2, ethanol)

21. (-) - cis-8,9-Dimethoxy-6- [4- (morpholin4-ylmethyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

3.0 g of (-) - cis-6- (4-chloromethylphenyl) -8.9 dimethoxy-1,2,3,4,4a, 10b-hexahydrophenanthridine (compound 20) and 2.2 g of potassium carbonate are suspended in 150 ml dimethylformamide, treated with 1.1 g of morpholine and stirred at 50 ° C for 3 hours. The suspension is treated with water and extracted with diethyl ether. The organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using petroleum ether (low boiling fraction) / ethyl acetate / triethylamine in a ratio of 6/3/1.

EF: C ₂₆ H ₃₂ ^ O ₃ , Mi: 420.56 Elemental analysis (x 0.4 H2O): calc .: C 73.00; H 7.73; N, 6.55, found: C, 73.25; H, 7.69; N, 6.22 Optical rotation: [a] _c ²⁰ = -73.5 ° (c = 0.2, ethanol)

22. (-) - cis-8,9-Dimethoxy-6- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -1,2,3,4,4a, 10H-hexahydrophenanthridine.

Obtained analogously to example 21 also using (starting material) (cis-6- (4-chloromethylphenyl) -8,9-dimethoxy1,2,3,4,4a, 10b-hexahydrophenanthridine (compound 20).

EF: C ₂₇ H ₃₅ No., O ₂ ; Mi: 433.60 'H-NMR (200 MHz, DMSO-b ₆ ): 1.1-1.95 ppm (t, 7H), 2.02-2.2 ppm (t, 1H)

2.15 ppm (8, 3H), 2.2-2.55 ppm (t, 8H), 2.57-2.78 ppm (t, 1H), 3.45 -3.59 ppm (t, 1H), 3.52 ppm (8, 2H), 3.6 ppm (8, 3H), 3.84 ppm (8, 3H), 6.72 ppm (8, 1H), 6.98 ppm (8, 1H), 7.35-7.54 ppm (t, 4H)

Optical rotation: | α | _υ ²⁰ = -66 ° (c = 0.2, ethanol)

23. (-) - cis-8,9-Dimethoxy-6- [4- (3-methylbutyryl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

I: 114-117 ° C

EF: C ₂₆ H ₃ ^ O ₃ ; Mi: 405.54

Elemental analysis:

calc .: C, 77.01; H 7.71; N, 3.45 found: C, 76.90; H 7.81; N 3.41 Optical rotation: [a] _c ²⁰ = -84.8 ° (c = 0.2, ethanol)

24. (-) - cis-8,9-Dimethoxy-6- (4-cyclopropylmethylcarbonylphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

Ts 93-98 ° C

EF: C ₂₆ H ₂ ^ O ₃ ; Mi: 403.53

Elemental analysis:

calc .: C, 77.39; H, 7.24; N, 3.47 found: C, 76.99; H, 7.22; N 3.34 Optical rotation: [a] _c ²⁰ = -76.3 ° (c = 0.2, ethanol)

25. (-) - cis-9-Ethoxy-8-methoxy-6- (4-benzoylphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₉ H ₂ ^ O ₃ ; Mi: 439.56

Elemental analysis:

calc .: C, 79.24; H, 6.65; N, 3.19, found: C, 78.94; H, 6.62; N 3.19

Optical rotation: [a] _c ²⁰ = -50 ° (c = 0.2, ethanol)

26. (-) - cis-8,9-Dimethoxy-6- [4- (4-methoxybenzoyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₉ H ₂₉ SO ₄ ; M ": 455.56

Elemental analysis:

calc .: C, 76.46; H 6.42; N, 3.07; found: C, 76.33; H 6.55; N 2.97 Optical rotation: | α | _υ ²⁰ = -61.7 ° (c = 0.2, ethanol)

27. (-) - cis-8,9-Dimethoxy-6- [4- (4-chlorobenzoyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: С ₂₈ Н ₂₆ ССО ₃ ; M ": 459.98

Elemental analysis (x 18 toluene): calc .: C 73.82; H 5.82; N, 2.93; C1 7.41 found: C 73.91; H 5.89; N, 2.80; C1 7.17 Optical rotation: [a] _c ²⁰ = -67.6 ° (c = 0.2, ethanol)

28. (-) - cis-8,9-Dimethoxy-6- [4- (3-chlorobenzoyl) phenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

I: 180-183.5 ° C

EF: С ₂₈ Н ₂₆ ССО ₃ ; M ": 459.98

Elemental analysis:

calc .: C 73.11; H 5.70; N, 3.04; C1 7.71 found .: C 72.93; H 5.76; N, 2.91; C1 7.84 Optical rotation: [a] _c ²⁰ = -14.3 ° (c = 0.2, ethanol)

29. (-) - cis-8,9-Dimethoxy-6- [4- (4-nitrobenzoyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₈ H _{2 &} S ₂ O ₅ ; M ": 470.53

Elemental analysis (x 0.28 H ₂ O): calc .: C 70.68; H 5.63; N, 5.89 detection: C, 70.79; H 5.85; N 5.77

Optical rotation: [a] _c ²⁰ = -65.1 ° (c = 0.2, ethanol)

30. (-) - cis-8,9-Dimethoxy-6- [4- (3-methoxybenzoyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

1 _pl : 146-148 ° C

EF: C ₂₉ H ₂ ^ O ₄ ; M ": 455.56

Elemental analysis:

calc .: C, 76.46; H 6.42; N, 3.07; found: C, 76.53; H 6.42; N 3.00

Optical rotation: [a] _s ²⁰ = -2.4 ° (s = 0.1, ethanol)

31. (-) - cis-8,9-Dimethoxy-6- [4- (4-cyanobenzoyl) phenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: C ₂₉ H _{2 &} S ₂ O ₃ ; M ": 450.54

Optical rotation: [a] _c ²⁰ = -56 ° (c = 0.2, ethanol)

32. (-) - cis-8,9-dimethoxy-6- [4- (pyridyl-4carbonyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₇ H _{2 &} S ₂ O ₃ ; M ": 426.52

Elemental analysis (x 0.3 N ₂ O):

calc .: C, 75.08; H, 6.21; N, 6.49. Found: C, 75.25; H, 6.32; N, 6.42

Optical rotation: [α] _ο ²⁰ = -72.9 ° (c = 0.2, ethanol)

33. (-) - cis-8,9-Dimethoxy-6- [3- (phenylsulfonyl) phenyl] -1,2,3,4,4a, 10b-hexahydrophenanthridine.

I: 164-166 ° C

EF: C ₂₇ H ₂ ^ O ₄ 8; M ": 461.58

Elemental analysis (x 0.15 H2O): calc .: C 69.89; H 5.92; N, 3.02; 8 6.91 found .: C 69.75; H 5.90; N, 3.22; 8 6.68 Optical rotation: [a] _c ²⁰ = -106.3 ° (c = 0.2, ethanol)

34. (-) - cis-8,9-Dimethoxy-6- [4- (phenylsulfonyl) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

1 _pl : 177-182 ° C

EF: C ₂₇ H ₂ ^ O ₄ 8; M ": 461.58

Elemental analysis:

calc .: C, 70.26; H 5.89; N, 3.03; 8.6.96 found: C 70.23; H 5.95; N, 2.89; 8 6.79

Optical rotation: [a] _s ²⁰ = -91.5 ° (s = 0.2, ethanol)

35. (-) - cis-8,9-Dimethoxy-6- (3-cyclopropylmethoxyphenyl) -1,2,3,4,4a, 10b-hexahydrophenanthridine.

1 _W : 54-61 ° C

EF: C ₂₅ H ₂ ^ O ₃ ; M ": 391.51

Elemental analysis:

calc .: C, 76.70; H 7.47; N, 3.58, found: C, 76.67; H, 7.61; N 3,56

Optical rotation: [a] _c ²⁰ = -80 ° (c = 0.2, ethanol)

36. (-) - cis-8,9-Dimethoxy-6- [3- (4-methoxyphenoxy) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: C ₂₈ H ₂ ^ O ₄ ; M ": 443.55

Elemental analysis:

calc .: C 75.82; H 6.59; N, 3.16. Found: C, 75.76; H 6.79; N 3.25

Optical rotation: [a] _s ²⁰ = -41.3 ° (s = 0.2, ethanol)

37. (-) - cis-8,9-Dimethoxy-6- [3- (pyrid-4yloxy) phenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: C ₂₆ H _{2 &} S ₂ O ₃ ; M ": 414.51

Elemental analysis (x 0.4 N ₂ O): calc .: C 74.05; H, 6.41; N, 6.64, found: C, 74.25; H 6.36; N, 6.42

Optical rotation: [a] _s ²⁰ = -35.2 ° (s = 0.2, ethanol)

38. (-) - cis-8,9-Dimethoxy-6- (3-cyclopropylmethoxy-4-ethoxyphenyl) -1,2,3,4,4a, 10H-hexahydrophenanthridine.

EF: C ₂₇ H ₃ ^ O ₄ ; M ": 435.57

Elemental analysis:

calc .: C, 74.45; H 7.64; N, 3.22. Found: C, 74.29; H, 7.67; N 3.14

Optical rotation: [a] _s ²⁰ = -87.8 ° (s = 0.2, ethanol)

39. (-) - cis-9-Ethoxy-8-methoxy-6 - [(3-cyclopropylmethoxy-4-ethoxy) phenyl] 1,2,3,4,4a, 10-hexahydrophenanthridine.

I: 102-105 ° C

EF: C ₂₈ H ₃₅ SO ₄ ; Mm: 449.60

Elemental analysis:

calc .: C 74.80; H 7.85; N, 3.12; found: C, 74.82; H 7.87; N 3.05

Optical rotation: [c] _s ²⁰ = -58.7 ° (s = 0.2, ethanol)

40. (-) - cis-9-Ethoxy-8-methoxy-6- [3,4bis (cyclopropylmethoxy) phenyl] -1,2,3,4,4a, 10H hexahydrophenanthridine.

EF: 0 ₃₀ Η ₃₇ ΝΟ ₄ ; Mm: 475.63

Elemental analysis:

calc .: C 75.76; H 7.84; N, 2.94 found: C, 75.66; H, 7.90; N 3.01

Optical rotation: [c] _s ²⁰ = -54.9 ° (s = 0.2, ethanol)

41. (-) - cis-8,9-Dimethoxy-6- [3,5-bis (cyclopropylmethoxy) phenyl] -1,2,3,4,4a, 10H hexahydrophenanthridine.

EF: C ₂₉ H ^ O ₄ ; Mm: 461.61

Elemental analysis (x 0.17 H ₂ O): calc .: C 74.96; H, 7.67; N, 3.01. Found: C, 74.99; H 7.63; N 2.97

Optical rotation: [a] _c ²⁰ = -65.9 ° (c = 0.2, ethanol)

42. (-) - cis-8,9-Dimethoxy-6- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) 1,2,3,4,4a, 10b-hexahydrophenanthridine.

EF: C ₂₆ H ₂₉ E ^ O ₄ ; Mm: 457.52

Elemental analysis:

calc .: C, 68.26; H 6.39; N, 3.06; G, 8.30, found: C, 68.27; H 6.45; N, 3.11; D 8.25 Optical rotation: | α | _υ ²⁰ = -91.3 ° (c = 0.2, ethanol)

43. (-) - cis-8,9-Dimethoxy-6- [3- (2-methoxyethoxy) -4-methoxyphenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: C ₂₅ H ₃ ^ O ₅ ; Mm: 425.53

Elemental analysis:

calc .: C, 70.57; H 7.34; N, 3.29. Found: C, 70.35; H 7.44; N 3.25 Optical rotation: [a] _c ²⁰ = -82.9 ° (c = 0.2, ethanol)

44. (-) - cis-8,9-Dimethoxy-6 - [(3-cyclobutoxy-4-methoxy) phenyl] -1,2,3,4,4a, 10L-hexahydrophenanthridine.

EF: С ₂₆ Нз ^ О ₄ ; MM: 421.54

Elemental analysis (x 0.17 H2O): calc .: C 73.55; H 7.44; N, 3.30. Found: C, 73.36; H 7.65; N 3.40

Optical rotation: [a] _s ²⁰ = -77.6 ° (s = 0.2, ethanol)

45. (-) - cis-8,9-Dimethoxy-6 - [(3-cyclopropylmethoxy-4-acetamido) phenyl] -1,2,3,4,4a, 10-hexahydrophenanthridine.

EF: C ₂₇ H ₃₂ ^ O ₄ ; MM: 448.57

Elemental analysis:

calc .: C, 70.60; H, 7.29; N, 6.10. Found: C, 70.80; H 7.35; N 5.88

Optical rotation: [a] _c ²⁰ = -80 ° (c = 0.2, ethanol)

46. (-) - cis-8,9-dimethoxy-6 - [(4-methoxy-3pyrrolidin-1-yl) phenyl] -1,2,3,4,4a, 10H-hexahydrophenanthridine.

EF: C ₂₆ H ₃₂ ^ O ₃ ; Mm: 420.56

Elemental analysis (x 0.23 H2O): calc .: C 73.51; H 7.71; N, 6.59, found: C, 73.75; H 7.71; N 6.35 Optical rotation: [a] _c ²⁰ = -89.5 ° (c = 0.2, ethanol)

47. (-) - cis-8,9-Dimethoxy-6- [4-methoxy-3 (2-oxopyrrolidin-1-yl) phenyl] -1,2,3,4,4a, 10H-hexahydrophenanthridine.

V 147-152 ° C

EF: C ₂₆ H ₃₀ ^ O ₄ ; Mm: 434,54

Elemental analysis (x 0.39 H ₂ O): calc .: C 70.71; H 7.03; N, 6.34. Found: C, 70.82; H, 7.00; N, 6.23 Optical rotation: [c] _s ²⁰ = -61.6 ° (s = 0.2, ethanol)

48. (-) - cis-8,9-Dimethoxy-6 - {[3- (2,5-dioxopyrrolidin-1-yl) -4-methoxy] phenyl} 1,2,3,4,4a, 10L- hexahydrophenanthridine.

2.5 g of (-) - cis-8,9-dimethoxy-6 - [(3-amino-4methoxy) phenyl] -1,2,3,4,4a, 10b-hexahydrophenanthridine and 680 mg of succinic anhydride are maintained at high temperature for 14 hours in a water separator. The solution was evaporated under reduced pressure and the residue was chromatographed on silica gel using toluene / dioxane / triethylamine in a ratio of 10/1/1. After evaporation of the fractions containing the product, 0.28 g of the title compound is obtained at 168-177 ° C.

EF: C ₂₆ H ₂₈ JO ₅ ; Mm: 448.52

Elemental analysis:

calc .: C, 69.63; H, 6.29; N, 6.25. Found: C, 69.29; H 6.28; N, 6.17 Optical rotation: [a] _c ²⁰ = -58.5 ° (c = 0.2, ethanol)

49. (-) - cis-8,9-Dimethoxy-6- (3-acetylphenyl) -1,2,3,4,4a, 10L-hexahydrophenanthridine.

1 _pl : 112.5-114 ° C

EF: C ₂₃ H ₂₅ yes ₃ ; Mm: 363,46

Elemental analysis:

calc .: C, 76.01; H 6.93; N, 3.85 found: C, 75.62; H, 6.90; N 3.83 Optical rotation: [a] _c ²⁰ = -168.7 ° (c = 0.2, ethanol)

50. (-) - cis-8,9-Dimethoxy-6- (4-propionylphenyl) -1,2,3,4,4a, 10b-hexahydrophenanthridine.

EF: C ₂₄ H ₂ ^ O ₃ ; MM: 377.49

Elemental analysis (x 0.24 H ₂ O): calc .: C 75.50; H, 7.25; N, 3.67 Found: C, 75.52; H 7.34; N 3.55 Optical rotation: [c] _s ²⁰ = -71.3 ° (s = 0.2, ethanol)

Source compounds.

A1. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-benzoylbenzamide.

4.0 g of (-) - cis-1,2-dimethoxy-4- (2-aminocyclohexyl) benzene (compound B4) was dissolved in 40 ml of methylene chloride and 10.0 ml of triethylamine. At RT, a solution of 4.9 g of benzophenone-4-carbonyl chloride in 100 ml of methylene chloride was added dropwise and after stirring overnight, the mixture was extracted using 50 ml of water each time, 2N. hydrochloric acid, saturated sodium bicarbonate solution and again water. The organic phase is dried using sodium sulfate and concentrated. 7.78 g of the title compound are obtained in the form of a crystallizing oil.

I: 119-122.5 ° C.

Optical rotation: [a] _s ²⁰ = -151.7 ° (s = 0.2, ethanol)

Using the starting compounds indicated below, analogously to Example A1, the following products are obtained.

A2. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-acetobenzamide.

ν 129-137 ° C.

Optical rotation: [α] _ο ²⁰ = -180.4 ° (c = 0.2, ethanol)

A3. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3-benzoylbenzamide in the form of an oil.

Optical rotation: [α] _ο ²⁰ = -162.9 ° (c = 0.2, ethanol)

A4. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-phenoxybenzamide.

I: 116-119.5 ° C.

Optical rotation: [a] _s ²⁰ = -151.7 ° (s = 0.2, ethanol)

A5. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3-phenoxybenzamide in the form of an oil.

Optical rotation: | α | _υ ²⁰ = -97.1 ° (c = 0.2, ethanol)

A6. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3-phenylthiobenzamide.

I: 157.5-159.5 ° C.

Optical rotation: [AC ²⁰ = -120.5 ° (c = 0.2, ethanol)

A7. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3-benzyloxybenzamide.

I: 131-133 ° C.

Optical rotation: [AC ²⁰ = -108.8 ° (c = 0.2, ethanol)

A8. (-) - cis-L- [2- (3,4-dimethoxyphenyl) diclohexyl] -3- (2-phenylethyloxy) benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -100.9 ° (s = 0.2, ethanol)

A9. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] - (3-cyclopentyloxy-4-methoxy) benzamide as a hardening oil.

Optical rotation: [AC ²⁰ = -117.3 ° (c = 0.2, ethanol)

A10. (-) - cis-L- [2- (3,4-dimethoxyphenyl) diclohexyl] - (3-cyclopropylmethoxy-4-benzoyloxy) benzamide.

I: 72.5-75.5 ° C.

Optical rotation: [a] _c ²⁰ = -118 ° (c = 0.2, ethanol)

A11. (-) -cis-L- [2- (3,4-dimethoxyphenyl) diclohexyl] - (3-benzyloxy-4-methoxy) benzamide.

I: 129.5-132 ° C.

Optical rotation: [a] _s ²⁰ = -108 ° (s = 0.2, ethanol)

A12. (-) -cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] - (3-cyclopropylmethoxy-4methoxy) benzamide as an oil.

Optical rotation: [α] _ο ²⁰ = -133.2 ° (c = 0.2, ethanol)

A13. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3-methanesulfonyloxybenzamide.

I: 155-158 ° C.

Optical rotation: [a] _s ²⁰ = -97.7 ° (s = 0.2, ethanol)

A14. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3- (p-toluenesulfonyloxy) benzamide in the form of a hardening oil.

Optical rotation: [a] _c ²⁰ = -60 ° (c = 0.2, ethanol)

A15. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] (3,4-biscyclopropylmethoxy) benzamide.

I: 90-98 ° C.

Optical rotation: [α] _ο ²⁰ = -119.1 ° (c = 0.2, ethanol)

A16. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (4-piperidinylcarbonyl) benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -128.3 ° (s = 0.2, ethanol)

A17. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (3-piperidinylcarbonyl) benzamide in the form of an oil.

Optical rotation: [a] _s ²⁰ = -88.6 ° (s = 0.2, ethanol)

A18. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-methoxycarbonylmethylbenzamide.

I: 88-98 ° C.

Optical rotation: [α] _ο ²⁰ = -116.2 ° (c = 0.2, ethanol)

A19. (-) - cis-L- [2- (3-ethoxy-4-methoxyphenyl) cyclohexyl] -4-chloromethylbenzamide.

I: 220-228 ° C.

A20. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-chloromethylbenzamide.

and: 94-97 ° C.

Optical rotation: [a] _s ²⁰ = -150.2 ° (s = 0.2, ethanol)

A21. (-) - cis-6- (4-chloromethylphenyl) -8,9dimethoxy-1,2,3,4,4a, 10b-hexahydro-phenanthridine.

Compare with example 20.

A22. (-) - cis-b- (4-chloromethylphenyl) -8,9dimethoxy-1,2,3,4,4a, 10b-hexahydrophenanthridine.

Compare with example 20.

A23. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (3-methylbutyryl) benzamide.

ν 118-120 ° C.

Optical rotation: [a] _s ²⁰ = -1b8.2 ° (s = 0.2, ethanol)

A24. (-) - cis-4- (2-cyclopropylmethylcarbonyl) -Y- [2- (3,4-dimethoxyphenyl) cyclohexyl] benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -151.4 ° (s = 0.2, ethanol)

A25. (-) - cis-L- [2- (3-ethoxy-4-methoxyphenyl) cyclohexyl] -4-benzoylbenzamide in the form of a hardening oil.

Optical rotation: [a] _c ²⁰ = -151 ° (c = 0.2, ethanol)

A2b. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (4-methoxybenzoyl) benzamide in the form of a hardening oil.

Optical rotation: [a] _c ²⁰ = -152.2 ° (c = 0.2, ethanol)

A27. (-) - cis-4- (4-chlorobenzoyl) -Y- [2- (3,4dimethoxyphenyl) cyclohexyl] benzamide.

ν 143-147.5 ° C.

Optical rotation: [a] _c ²⁰ = -173.3 ° (c = 0.2, ethanol)

A28. (-) - cis-4- (3-chlorobenzoyl) -Y- [2- (3,4dimethoxyphenyl) cyclohexyl] benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -14b, 8 ° (s = 0.2, ethanol)

A29 (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (4-nitrobenzoyl) benzamide in the form of a hardening oil.

Optical rotation: [a] _c ²⁰ = -147, b ° (c = 0.2, ethanol)

A30. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (3-methoxybenzoyl) benzamide in the form of a hardening oil.

Optical rotation: [α] _ο ²⁰ = -140.9 ° (c = 0.2, ethanol)

A31. (-) - cis-4- (4-cyanobenzoyl) -Y- [2- (3,4dimethoxyphenyl) cyclohexyl] benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -143.3 ° (s = 0.2, ethanol)

A32. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4- (pyrid-4-ylcarbonyl) benzamide.

I: 109-117 ° C

Optical rotation: [a] _s ²⁰ = -193.7 ° (s = 0.2, ethanol)

A3 3. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3-phenylsulfonylbenzamide in the form of a hardening oil.

Optical rotation: | α | _υ ²⁰ = -48.8 ° (c = 0.2, ethanol)

A34. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-phenylsulfonylbenzamide.

Optical rotation: [α] _ο ²⁰ = -134.1 ° (c = 0.2, ethanol)

A35. (-) - cis-3-cyclopropylmethoxy-Y- [2 (3,4-dimethoxyphenyl) cyclohexyl] benzamide.

V 84.5-9b ° C

Optical rotation: [α] _ο ²⁰ = -95.5 ° (c = 0.2, ethanol)

A3b. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3- (4-methoxyphenoxy) benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -110.9 ° (s = 0.2, ethanol)

A37 (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -3- (pyrid-4-yloxy) benzamide.

! _w : 173-17b ° C

Optical rotation: [α] _ο ²⁰ = -110.7 ° (c = 0.2, ethanol)

A38. (-) - cis-3-cyclopropylmethoxy-Y- [2 (3,4-dimethoxyphenyl) cyclohexyl] -4-ethoxybenzamide.

V 99-101 ° C

Optical rotation: [a] _s ²⁰ = -140.5 ° (s = 0.2, ethanol)

A39. (-) - cis-3-cyclopropylmethoxy-4ethoxy-Y- [2- (3-ethoxy-4-methoxyphenyl) cyclohexyl] benzamide.

! _W : 98-100 ° C

Optical rotation: [a] _s ²⁰ = -119.5 ° (s = 0.2, ethanol)

A40. (-) - cis-3,4-bis (cyclopropylmethoxy) No. [2- (3-ethoxy-4-methoxyphenyl) cyclohexyl] benzamide.

! _W : 91-98 ° C

Optical rotation: [α] _ο ²⁰ = -107.1 ° (c = 0.2, ethanol)

A41. (-) - cis-3,5-bis (cyclopropylmethoxy) No. [2- (3,4-dimethoxyphenyl) cyclohexyl] benzamide in the form of a hardening oil.

Optical rotation: [a] _c ²⁰ = -71, b ° (c = 0.2, ethanol)

A42. (-) - cis-3-cyclopropylmethoxy-4difluoromethoxy-Y- [2- (3,4-dimethoxyphenyl) cyclohexyl] benzamide.

! _W : 90-91 ° C

Optical rotation: [a] _s ²⁰ = -92.5 ° (s = 0.2, ethanol)

A43. (-) - cis-L- [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-methoxy-3- (2-methoxyethoxy) benzamide.

Optical rotation: [α] _ο ²⁰ = -130.2 ° (c = 0.2, ethanol)

A44. (-) - cis-3-cyclobutoxy-Y- [2- (3,4dimethoxyphenyl) cyclohexyl] -4-methoxybenzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -135.3 ° (s = 0.2, ethanol)

A45. (-) - cis-4-acetamido-3-cyclopropylmethoxy-Y- [2- (3,4-dimethoxyphenyl) cyclohexyl] benzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -153.3 ° (s = 0.2, ethanol)

A46. (-) - cis-No. [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-methoxy-3-pyrrolidin-1ylbenzamide in the form of a hardening oil.

Optical rotation: [a] _c ²⁰ = -125.1 ° (c = 0.2, ethanol)

A47. (-) - cis-No. [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-methoxy-3 - (2-oxopyrrolidin1-yl) benzamide.

Optical rotation: [a] _s ²⁰ = -113.5 ° (s = 0.2, ethanol)

A48. (-) - cis-8,9-dimethoxy-6 - [(3-amino-4methoxy) phenyl] -1,2,3,4,4a, 10b-hexahydrophenanthridine.

Obtained from (-) - cis-No. [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-methoxy-3-nitrobenzamide [optical rotation: [a] _with ²⁰ = -119.1 ° (c = 0.2 , ethanol)] as described for the preparation of compound 1.

EF: C ₂₂ H ₂₄ ^ O ₅ ; Md: 396.45

Elemental analysis:

calc .: C, 66.65; H, 6.10; N, 7.07. Found: C, 67.06; H, 6.21; N 6.77 Optical rotation: [a] _s ²⁰ = -137.5 ° (s = 0.2, ethanol)

A49. (-) - cis-3-acetyl-No. [2- (3,4-dimethoxyphenyl) cyclohexyl] benzamide in the form of a hardening oil.

Optical rotation: [α] _Β ²⁰ = -127.1 ° (c = 0.2, ethanol)

A50. (-) - cis-No. [2- (3,4-dimethoxyphenyl) cyclohexyl] -4-propionylbenzamide in the form of a hardening oil.

Optical rotation: [a] _s ²⁰ = -160 ° (s = 0.2, ethanol)

B1. (+/-) - cis-2-ethoxy-1-methoxy-4- (2aminocyclohexyl) benzene.

40.0 g (+/-) - cis-2-ethoxy-1-methoxy-4- (2 nitrocyclohex-4-enyl) benzene (compound B1) are dissolved in 1000 ml of ethanol and 500 ml of tetrahydrofuran, treated with 10 g of Raney nickel and within 4 days hydrogenated in an autoclave under a hydrogen pressure of 100 bar. After filtering and removing the solvent under vacuum, 35.9 g of the title compound are obtained in the form of a hardening oil.

B2. (-) - cis-1-methoxy-2-ethoxy-4- (2-aminocyclohexyl) benzene.

65.0 g (+/-) - cis-1-methoxy-2-ethoxy-4- (2aminocyclohexyl) benzene and 100.0 g (+) - O, O'dibenzoyl tartaric acid are dissolved in 900 ml of dioxane and 900 ml of methyl isobutyl ketone and at RT, the solution was stirred overnight. The solid material is filtered off under vacuum, washed with stirring with 500 ml of acetone and 1000 ml of ethyl acetate, again filtered off under vacuum and dried. The product is treated with 600 ml of 2n. sodium hydroxide solution and extracted with ethyl acetate. The organic phase is washed with water, dried using sodium sulfate and concentrated under reduced pressure. 15.3 g of the title compound are obtained as a pale yellow oil.

Optical rotation: [a] _s ²⁰ = -47.5 ° (s = 0.2, ethanol)

B3. (+/-) - cis-1,2-dimethoxy-4- (2-aminocyclohexyl) benzene.

125 g of (+/-) - cis-1,2-dimethoxy-4- (2 nitrocyclohexyl) benzene and 120.0 g of powdered or granular zinc are suspended in 1300 ml of ethanol. While boiling, 220 ml of acetic acid are added dropwise. The precipitate was filtered off with suction and washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid and extracted with toluene. The aqueous phase was made basic using a 50% strength sodium hydroxide solution, the precipitate was filtered off with suction and the filtrate was extracted with toluene. The organic phase is dried using sodium sulfate and concentrated. 98 g of the title compound are obtained in the form of a crystallizing oil.

Another variant.

8.5 g of (+/-) - cis-1,2-dimethoxy-4- (2-nitrocyclohexyl) benzene are dissolved in 400 ml of methanol and treated with CT for 7 hours with 7 ml of hydrazine hydrate and 2.5 g of Raney nickel in the form of portions. After stirring at RT overnight, the reaction mixture was filtered, the filtrate was concentrated, and the residue was chromatographed on silica gel using a mixture of toluene / ethyl acetate / triethylamine in a ratio of 4/2 / 0.5. The title compound was obtained as an oil.

B4. (-) - cis-1,2-dimethoxy-4- (2-aminocyclohexyl) benzene.

12.0 g of (+/-) - cis-1,2-dimethoxy-4- (2-aminocyclohexyl) benzene and 6.2 g of (-) - mandelic acid are dissolved in 420 ml of dioxane and 60 ml of tetrahydrofuran and with CT solution stirred overnight. The solid material is filtered off with suction, dried, treated with 100 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried using sodium sulfate and concentrated under reduced pressure. 4.8 g of the title compound are obtained with 1 _PL : 80-81.5 ° C.

Specific rotation: [a] _s ²⁰ = -58.5 ° (s = 0.1, ethanol)

IN 1. (+/-) - cis-2-ethoxy-1-methoxy-4- (2 nitrocyclohex-4-enyl) benzene.

89.25 g of (+/-) trans-2-ethoxy-1-methoxy-4 (2-nitrocyclohex-4-enyl) benzene (compound G1) and 37 g of potassium hydroxide are dissolved in 500 ml of absolute ethanol. Then, a solution of 23.5 ml of concentrated sulfuric acid in 120 ml of absolute ethanol was added dropwise so that the temperature inside the reactor did not exceed -2 ° С. After stirring for 1 h, the mixture was introduced into 4 l of ice water and the precipitate was filtered off with suction, washed with water and dried.

I: 66-67 ° C.

AT 2. (+/-) - cis-1,2-dimethoxy-4- (2-nitrocyclohex-4-enyl) benzene.

10.0 g of (+/-) trans-1,2-dimethoxy-4- (2 nitrocyclohex-4-enyl) benzene and 20.0 g of potassium hydroxide are dissolved in 150 ml of ethanol and 35 ml of dimethylformamide. A solution of 17.5 ml of concentrated sulfuric acid in 60 ml of ethanol is added dropwise so that the temperature inside the reactor does not exceed 4 ° C. After stirring for 1 h, the mixture was introduced into 1 L of ice water, the precipitate was filtered off with suction, washed with water and dried, and the crude product was recrystallized from ethanol. 8.6 g of the title compound are obtained with 1 _{|| L} : 82.5-84 ° C.

OT. (+/-) - cis-1,2-dimethoxy-4- (2-nitrocyclohexyl) benzene.

8.4 g of (+/-) - cis-1,2-dimethoxy-4- (2-nitrocyclohex-4-enyl) benzene are dissolved in 450 ml of methanol, treated with 2 ml of concentrated hydrochloric acid and after adding 500 mg of 10% - Nb RB / C hydrogenated. The reaction mixture was filtered and the filtrate was concentrated.

Щ 84-86.5 ° С.

G1. (+/-) - trans-2-ethoxy-1-methoxy-4- (2 nitrocyclohex-4-enyl) benzene.

110 g of 3-ethoxy-2-methoxy-s-nitrostyrene (compound D1) and 360 mg of hydroquinone are suspended in 360 ml of absolute toluene and 180 ml of liquid 1,3-butadiene are treated at -70 ° C. The mixture is stirred at 160-180 ° C for 6 days in an autoclave, and then cooled. The product is washed with stirring with ethanol, filtered off under suction and dried.

I: 130-131 ° C.

G2. (+/-) - trans-1,2-dimethoxy-4- (2-nitrocyclohex-4-enyl) benzene.

50.0 g of 3,4-dimethoxy-s-nitrostyrene and 1.0 g (9.1 mmol) of hydroquinone are suspended in 200 ml of absolute toluene and 55 g (1.02 mol) of liquid 1.3 are treated at -70 ° C. butadiene. The mixture was stirred at 160 ° C. for 6 days in an autoclave, and then cooled. A quantity of solvent is removed in a rotary evaporator, and the precipitate formed is filtered off with suction and recrystallized from ethanol.

I: 113.5-115.5 ° C.

D1. 3-ethoxy-2-methoxy-n-nitrostyrene.

236 g of 3-ethoxy-2-methoxybenzaldehyde, 101 g of ammonium acetate and 320 ml of nitromethane at 100 ° C are kept for 4 hours in 655 ml of glacial acetic acid. The solution was introduced into 5 l of ice water and the precipitate was filtered off with suction, washed with water and dried. 1 _pl : 132133 ° C.

D 2. 3,4-dimethoxy-s-nitrostyrene.

207.0 g of 3,4-dimethoxybenzaldehyde, 100.0 g of ammonium acetate and 125 ml of nitromethane are boiled for 3-4 hours in 1.0 l of glacial acetic acid. After cooling in an ice bath, the precipitate was filtered off with suction, washed with glacial acetic acid and petroleum ether, and dried. 1 _pl : 140-141 ° C. Yield: 179.0 g.

Possibility of technical application.

Compounds in accordance with the invention have valuable pharmacological properties that make them technically usable. As selective inhibitors of cyclonucleotide phosphodiesterase (PDE) (namely, type 4), they, on the one hand, are suitable as bronchial drugs (for the treatment of airway obstruction due to their dilating effect, as well as due to increased respiratory rate or respiratory stimulation) and for elimination of erectile dysfunctions due to their vasodilating effect, and on the other hand, especially in the treatment of mainly inflammatory disorders, for example, respiratory tract (asthma prevention), skin, the central nervous system, intestines, eyes and joints, which are caused by mediators, such as histamine, TAF (platelet-activating factor), arachidonic acid derivatives, such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha, beta and gammainterferons , tumor necrosis factor (TNF), or oxygen and protease radicals. The compounds of the invention are characterized by low toxicity, good enteral absorption (high bioavailability), a large therapeutic spectrum of activity and the absence of significant side effects.

Due to their PDE-inhibiting properties, the compounds of the invention can be used in conventional therapy, veterinary medicine and clinical medicine, where they can be used, for example, in the treatment and prevention of the following diseases: acute and chronic (especially inflammatory and allergen-induced) respiratory disorders of various origins ( bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD); dermatoses (especially proliferative, inflammatory and allergic types), such as psoriasis (common), toxic and allergic contact eczema, atopic dermatitis, seborrheic eczema, lichen versus chronic, solar erythema, pruritus in the anogenital region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and continuous pyoderma, endogenous and exogenous acne, rosacea and other proliferative, inflammatory and allergic skin diseases; diseases associated with an excess of TNF and leukotrienes, for example, arthritis-type diseases (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritis complications), diseases of the immune system (AIDS, multiple sclerosis), implant-to-host reaction, transplant rejection reactions, shock symptoms ( septic shock, endotoxic shock, gram-negative sepsis, toxic shock) and LKE8 (adult respiratory distress syndrome) and extensive inflammation in the gastrointestinal region (Crohn’s disease and non-specific ulcerative colitis); diseases caused by allergic and / or chronic defective immunological reactions in the upper respiratory tract (pharynx, nose) and adjacent areas (sinuses, eyes), such as, for example, allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis and nasal polyps; and cardiac disorders that can be treated with PDE inhibitors, such as heart failure, or diseases that can be treated with the tissue healing effect of PDE inhibitors, such as erectile dysfunction or colic of the kidneys and ureter in combination with kidney stones. In addition, the compounds of the invention can be used to treat diabetes insipidus, disorders caused by impaired brain metabolism, such as cerebral extinction, senile dementia (Alzheimer's dementia), post-infarction dementia, or alternative CNS disorders, such as depression or arteriosclerosis dementia.

Another object of the invention is a method for the treatment of mammals, including humans, which suffer from one of the aforementioned diseases. This method includes the introduction into the body of a diseased mammal a therapeutically effective and pharmacologically acceptable amount of one or more compounds in accordance with the invention.

The invention further relates to compounds according to the invention for use in the implementation of a method for treating mammals, including humans, that suffer from one of the aforementioned diseases. This method includes the introduction into the body of a diseased mammal a therapeutically effective and pharmacologically acceptable amount of one or more compounds in accordance with the invention.

Furthermore, the invention provides compounds according to the invention for use in the treatment and / or prophylaxis of diseases, in particular the diseases mentioned.

Likewise, an object of the invention is the use of the compounds in accordance with the invention for the manufacture of drugs which are used in the treatment and / or prevention of the aforementioned diseases.

In addition, the invention provides medicaments for the treatment and / or prophylaxis of the aforementioned diseases, which include one or more compounds in accordance with the invention.

Another object of the invention is an industrial product consisting of a conventional secondary packaging, a primary package containing medicines (for example, ampoules or blister packs) and optional enclosed packaging. Medicines exhibit an antagonistic effect on type 4 cyclonucleotide phosphodiesterase (PDE4) and help to alleviate the symptoms of diseases associated with type 4 cyclonucleotide phosphodiesterase. The suitability of drugs for the prevention and treatment of diseases associated with type 4 cyclonucleotide phosphodiesterase is indicated on the secondary packaging and / or technical product and medicines containing one or more compounds according to the invention of formula I. Secondary packaging, primary the first set containing a drug, and packaging is thus embedded are common concepts to a person skilled in the use of drugs of this type.

Medicines are prepared according to methods that are known and familiar to a person skilled in the art. As medicines, the compounds in accordance with the invention (i.e., active compounds) are either used alone, or, preferably, in combination with acceptable pharmaceutical excipients, for example in the form of tablets, coated tablets, capsules, suppositories, plasters, emulsions, suspensions, gels or solutions, and the appropriate content of the active compound is in the range from 0.1 to 95%.

If based on our own knowledge of a qualified specialist in this field of technology, then he knows the excipients that are acceptable for the preparation of target pharmaceutical compositions. In addition to solvents, gelling agents, ointment bases and other carriers for the active compounds, for example, antioxidants, dispersants, emulsifiers, preservatives, solubilizers or penetration promoting agents can be used.

For the treatment of respiratory diseases, in a preferred embodiment, the compounds of the invention are also administered by inhalation. To this end, they are administered either directly in powder form (preferably in finely divided form) or by spraying the solutions or suspensions that contain them. As regards preparations and administration forms, for example, see EP 163965.

For the treatment of dermatoses, the compounds in accordance with the invention are used, in particular, in the form of those drugs which are suitable for topical application. For the preparation of medicaments, the compounds in a preferred embodiment of the invention (i.e., active compounds) are mixed with suitable pharmaceutical excipients and further processed to obtain acceptable pharmaceutical compositions. Suitable pharmaceutical compositions that may be mentioned are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels and solutions.

Medicines in accordance with the invention are prepared according to methods that are known. The dosage of the active compounds is carried out, adhering to approximately the same values that are usual for PDE inhibitors. For example, topical formulations (in particular, such as ointments) used in the treatment of dermatoses include active compounds in a concentration of, for example, from 0.1 to 99%. The dose for administration by inhalation is usually in the range of 0.1 to 3 mg / day. In the case of systemic therapy, the usual dose (for oral or intravenous administration) ranges from 0.03 to 3 mg / kg / day.

Biological research.

When studying PDE4 inhibition at the cellular level, it is especially important to activate inflamed cells. For example, one can note the production of superoxide induced by EUBP (β-formylmethionyl-leucylphenylalanine) in neutrophilic granulocytes, which can be determined using luminol-dependent chemiluminescence Biggs! shesyashzsh. Ιη 1 type 1 zebes 1992, 57, 47-76; fuck SoNeu CS (Magse1 Oeskeg, 1ps., No. \ ν Wogk-Wazk-Nopd Kopd)].

Substances that inhibit chemiluminescence, cytokine secretion and the secretion of inflammatory mediators in inflamed cells, mainly in neutrophilic and eosinophilic granulocytes, T-lymphocytes, monocytes and macrophages, are PDE4-inhibiting substances. This isoenzyme of the phosphodiesterase family is represented mainly in granulocytes. Its inhibition leads to an increase in the concentration of intracellular cyclic AMP and, thus, to inhibition of cell activation. Thus, inhibition of PDE4 by the compounds of the invention is a major indicator of the suppression of inflammatory processes. ! (S1etbusζ MA Soi1b ^ 8οeηζute-8e1esbνe ryo8ryob1e8 ega8e shYyogz gepbeg gopsobba OSU yegaru gebipbap t 1ye Bea Hea og gopsYa1 aChyta V1osyet.Ryagtaso1 1992, 43, 2041-2051;!!!!!?. Togryu T1, etc., Ryo8rbob1e8. ! Eg8e SHYyogs: ne \ u orroblshbez without Gog 1gea1te1 oG aChita. Tyogakh 1991, 46, 512523; 8sinb1 S et al., 2agbauebpe: a sysys AMR POE 3/4 1py1byog. Б й ие АМ 1991 АМ 68 68 68 68 68 68 68 68 68 уп уп уп уп со уп со уп уп уп уп со уп уп уп уп АМ со со со АМ со уп АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ АМ Og Rey 18oepζute rgoGLee m se11e APB bzziez Ly ryagtaso1od1sa1 tebyube 1H Ryoeryob1ee1egaee shYyogz, 2140 Tye Napbook 1ttiporyagtaso1odu Og, Asabetk Picea, 1966;. Nake1tapp A et al Eηζutabs APB Gipsbopa1 aeres1e bia1-8e1esbue REE3 Og / 4-1H shy1yog8 Ryoeryob1ee1egaee.. shy1b11oge, 147160. Thieh Nabbok oG 1mtiporyagtasodu, Asabetk Przee, 1996).

Inhibition of PDE4 activity. Methodology.

The activity test is carried out according to the method of Bauer and Schwabe, which is adapted for a microtiter plate (Naipup8sitkbeebd in Agsy. Ryagtaso. 1980, 311, 193198). PDE reaction is carried out at the first stage. At the second stage, the resulting 5'-nucleotide is cleaved with the 5'-nucleotidase of snake venom from Clo1a1 aboh to obtain an uncharged nucleoside. In a third step, the nucleoside is separated from the remaining charged substrate on ion exchange columns. Columns are eluted directly into miniprobes, to which 2 ml of scintillation fluid are additionally added, using 2 ml of 30 mM ammonium formate (pH 6.0) for counting.

The inhibitory values obtained for the compounds of the invention [inhibitory concentration as -1od 1C ₅₀ (mol / L)] are presented in Table. A, in which the numbers of the compounds correspond to the numbers of the samples.

Table A Inhibition of PDE4 activity

Compound -1ode IK50 one 7.82 2 7.27 3 8.64 4 7.52 5 8.54 7 8.40 8 8.41 nine 7.79

10 8.09 eleven 8.03 12 7.80 thirteen 8.33 14 8.44 fifteen 7.89 sixteen 8.02 17 8.13 eighteen 7.49 nineteen 8.59 21 7.35 22 7.27 23 7.5 24 7.48 25 8.87 26 7.46 27 7.3 28 7.61 29th 7.28 thirty 7.94 31 7.8 32 7.45 33 8.23 34 7.89 35 7.43 36 8.78 37 7.92 38 7.47 39 8.87 40 8.65 41 8.03 42 7.43 44 7.58 45 8.04 46 7.16 47 7.33 48 7.67 49 7.17 fifty 7.98

CLAIM

Claims (10)

1. The compounds of formula I in which R1 represents hydroxyl, C1-C ₄ alkoxy, C ₃ -C ₇ cycloalkoxy, C ₃ -C ₇ cycloalkylmethoxy or completely or predominantly fluorine-substituted Cp -C ₄ alkoxy, R2 is hydroxy, _C1-C4 alkoxy, C3-S7tsikloalkoksi, C3-S7tsikloalkilmetoksi or completely or predominantly fluorine-substituted C1-C4 alkoxy, or in which R1 and R2 together are _C1-C2 alkylenedioxy, K3 is a hydrogen atom or C1C4 alkyl, K31 is hydrogen or S1S4alkil, or in which R3 and K31 together represent _C1-C4 alkylene group, K4 is a hydrogen atom or C1C4 alkyl, K5 represents a hydrogen atom, K51 represents a hydrogen atom, or in which K5 and K51 together represent an additional bond, K6 is O-K7, 8-K8, C (O) -K9, CH2K10, 8 (O) ₂ -aryl, O-8 (O) ₂ -K11, pyrrolidin-1-yl, pyrrolidin-1-yl-2 -one, pyrrolidin-1-yl-2,5-dione, piperidin-1-yl, piperidin-1-yl-2-one or piperidin-1-yl-2,6-dione, where K7 is C3-C7cycloalkyl, S3S ₇ cycloalkylmethyl, C 1 -C ₄ alkoxy-C 1 -C ₄ alkyl, aryl or _phenyl-C1-C4 alkyl, R8 represents a hydrogen atom, C1C ₄ alkyl, C1C ₄ alkylcarbonyl, arylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl, R9 is _C1-C4 alkyl, _{C3-C7cycloalkyl,} C3-S7tsikloalkilmetil, 1pirrolidinil, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, K10 is hydroxyl, halogen, cyano, carboxyl, _C1-C4 alkoxy, phenoxy, C 1 -C 4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-S4alkilaminokarbonil, Ν (Κ15) Κ16 or _C1-C4 alkylcarbonylamino, and K11 is C ₁ -C ₄ alkyl, amino, mono or di-C ₁ -C ₄ alkylamino or aryl, aryl is phenyl, pyridyl or K12-substituted phenyl, where K12 denotes hydroxyl, a halogen atom, carboxyl, nitro, amino, cyano, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylcarbonyloxy or aminocarbonyl, K13 represents a hydrogen atom, hydroxyl, a halogen atom, a cyano, nitro, amino group, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy, fully or predominantly fluoro-substituted C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl, C (O) OK14, C (O) -Y (K15) K16, Ν (Κ17) Κ18, 8 (O) ₂ -K19, 8 (O) ₂ -I (K15) K16 or has one of the values of K6, where K14 represents a hydrogen atom, C1-4 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylmethyl, K15 is a hydrogen atom, C1C4 alkyl, C3-C7 cycloalkyl or C3C7 cycloalkylmethyl, K16 represents a hydrogen atom, C ₁ C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkylmethyl or aryl, or when K15 and K16 together and including the nitrogen atom to which they are bonded, represent 1 pyrrolidinyl, 1-piperidinyl, 1 piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical, K17 is hydrogen, C1C ₄ alkyl, 8 (O) -K19 ₂ or 8 (O) ₂ -aryl, K18 is _C1-C4 alkyl, _{C1-C4-alkylcarbonyl,} C3-S7tsikloalkilkarbonil, S3S tsikloalkilmetilkarbonil _7, 8 (OH) ₂ or -K19 8 (O) ₂ -aryl, and K19 is C ₄ -C ₄ alkyl, K20 is hydrogen, hydro xylitol, halogen atom, nitro, amino, C1C ₄ alkyl, trifluoromethyl, C1C ₄ alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, C3-S7tsikloalkoksi, S3S ₇ cycloalkylmethoxy, CH ₂ -K10, carboxyl , C _p C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C ₁ -C ₄ alkylcarbonylamino or aminocarbonyl, as well as salts, окс-oxides and salts of Ν-oxides of these compounds. 2. The compounds according to claim 1 of formula I, in which K1 is C ₄ -C ₂ alkoxy, C ₃ C5 cycloalkoxy, C3-C5 cycloalkylmethoxy or fully or predominantly fluoro-substituted C1-C2 alkoxy, R2 is _{C1-C2-alkoxy, C3} S5tsikloalkoksi, C3-S5tsikloalkilmetoksi or completely or predominantly fluorine-substituted C ₁ -C ₂ alkoxy, KZ stands for hydrogen atom, KZ 1 denotes a hydrogen atom, K4 is a hydrogen atom or C ₁ C2 alkyl, K5 represents a hydrogen atom, K51 represents a hydrogen atom or in which K5 and K51 together represent an additional bond, K6 is O-K7, 8-K8, C (O) -K9, SSCK10, 8 (O) ₂ -aryl, O-8 (O) ₂ -K11, pyrrolidin-1-yl, pyrrolidin-1-yl-2 -one or pyrrolidin-1-yl2,5-dione, where K7 is C3-C7 cycloalkyl, C3C ₇ cycloalkylmethyl, C ₁ -C ₄ alkoxy-C ₄ -C ₄ alkyl, aryl or phenyl-C1-C ₄ alkyl, K8 is a hydrogen atom, C1-4 alkyl, acetyl, phenylcarbonyl, trifluoromethyl or phenyl, R9 is C1-C ₄ alkyl, C ₃ -C ₇ cycloalkyl, C3-S7tsikloalkilmetil, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, K10 is a halogen atom, carboxyl, _C1-C4 alkoxy, phenoxy, C ₄ -C ₄ alkoxycarbonyl, aminocarbonyl, mono- or di-C ₁ -C ₄ alkylaminocarbonyl, Ν (Κ15) Κ16 or C ₁ S4alkilkarbonilaminogruppu and K11 is C1-C4 alkyl, mono- or diC1-C4 alkylamino or aryl, aryl is phenyl, pyridyl or K12 substituted phenyl, where K12 represents a halogen atom, a carboxyl, nitro, amino, cyano group, C1-C4 alkyl, trifluoromethyl or C1-C4 alkoxy, K13 is hydrogen, hydroxyl, halogen, cyano, nitro, amino, C1-C4alkyl, trifluoromethyl, C1-C4 alkoxy, completely or predominantly fluorine-substituted C1-C4 alkoxy, phenyl, phenyl-C1C ₄ alkyl, C (O) OK14, C (O) -Y (K15) K16, Ν (Κ17) Κ18, 8 (О) ₂ -К19, 8 (О) ₂ -Ы (К15) К16 or has one of the values of К6, where K14 represents a hydrogen atom or C1C4 alkyl, K15 represents a hydrogen atom or C1C4 alkyl, K16 represents a hydrogen atom, C1C4 alkyl or aryl, or when K15 and K16, together and including the nitrogen atom to which they are attached, represent a 1 piperidyl, 1-piperazinyl, 1-methylpiperazin-4-yl or 4-morpholinyl radical, K17 is hydrogen, C1C ₄ alkyl, 8 (O) -K19 ₂ or 8 (O) ₂ -aryl, K18 is C1-C4alkyl, S1S4alkilkarbonil, C3-S7tsikloalkilkarbonil, C ₃ -C ₇ tsikloalkilmetilkarbonil, 8 (OH) ₂ or 8 -K19 (O) ₂ -aryl, and K19 is _C1-C4 alkyl, K20 denotes a hydrogen atom, hydroxyl, a halogen atom, a nitro, amino group, C ₁ C ₄ alkyl, trifluoromethyl, C ₄ -C ₄ alkoxy, fully or predominantly fluoro-substituted C ₁ -C ₄ alkoxy, C ₃ -C ₇ cycloalkoxy, C ₃ -C ₇ cycloalkylmethoxy, carboxyl, C 1 -C C ₄ alkoxycarbonyl or C1-C4 alkylcarbonyloxy, as well as salts, окс-oxides and salts of Ν-oxides of these compounds. 3. The compounds according to claim 1 of formula I, in which R1 is _{C1-C2-alkoxy,} K2 is C ₄ -C ₂ alkoxy, KZ, K31, K4, K5 and K51 denote hydrogen atoms, K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10, 8 (O) _2- phenyl, O-8 (O) ₂ -K11, pyrrolidin-1yl, pyrrolidin-1-yl-2 -one or pyrrolidin-1yl-2,5-dione, where K7 is C3-C5 cycloalkyl, C3C5 cycloalkylmethyl, C1-C2 alkoxy-C1-C2 alkyl, aryl or phenyl-C1-C2 alkyl, K8 is phenyl, K9 is C1-C4 alkyl, C3C ₅ cycloalkylmethyl, 1-piperidinyl or aryl, K10 is a halogen atom, C1C ₄ alkoxycarbonyl or Ν (Ρ15) Ρ16. but K11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or K12 substituted phenyl, where K12 is C1-C4 alkyl, C1-C4 alkoxy, a halogen atom, a nitro or cyano group, K15 is C1-C4 alkyl, and K16 is C1-C4 alkyl or K15 and K16, together and including the nitrogen atom to which they are bonded, denote 1 piperidinyl, 1-piperazinyl, 1 methylpiperazin-4-yl or 4-morpholinyl radical, and in which either K13 represents a hydrogen atom, C1C ₄ alkoxy, fully or predominantly fluoro-substituted C1 Is a C2 alkoxy, C1-C4 alkylcarbonylamino group, and K20 is a hydrogen atom, or K13 is a hydrogen atom, and K20 is C3-C5 cycloalkoxy or C3C5 cycloalkylmethoxy, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds. 4. The compounds according to claim 1 of formula I, in which K1 is C1-C2 alkoxy, K2 is C1-C2 alkoxy, K3, K31, K4, K5 and K51 denote hydrogen atoms, K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10, 8 (O) _2- phenyl, O-8 (O) ₂ -K11, pyrrolidin-1yl or pyrrolidin-1-yl-2 -on where K7 is cyclobutyl, cyclopentyl, cyclopropylmethyl, 2-methoxyethyl, phenyl, 4methoxyphenyl, benzyl, phenethyl or pyridyl, K8 is phenyl, K9 is methyl, ethyl, isobutyl, cyclopropylmethyl, 1-piperidinyl or aryl, K10 is methoxycarbonyl, morpholin-4-yl or 1-methylpiperazin-4-yl, and K11 is methyl or 4-methylphenyl, aryl is phenyl, pyridyl or K12 substituted phenyl, where K12 is methoxy, a halogen atom, nitro or cyano, and in which either K13 is a hydrogen atom, methoxy, ethoxy, difluoromethoxy or acetylamino, and K20 is a hydrogen atom, or K13 is a hydrogen atom, and K20 is cyclopropylmethoxy, as well as salts, Ν-oxides and salts of Ν-oxides of these compounds. 5. The compound according to claim 1 of formula I, in which K1 is hydroxyl, C1-C4 alkoxy, C3-C7 cycloalkoxy, C3-C7 cycloalkylmethoxy or fully or predominantly fluoro-substituted C ₁ -C ₄ alkoxy, K2 is hydroxyl, C1-C4 alkoxy, C ₃ -C ₇ cycloalkoxy, C ₃ -C ₇ cycloalkylmethoxy or fully or predominantly fluoro-substituted C ₁ -C ₄ alkoxy, or in which K1 and K2 together represent a C ₁ C ₂ alkylenedioxy group, K3 is a hydrogen atom or C1C4 alkyl, K31 denotes a hydrogen atom or C1C4 alkyl, or in which K3 and K31 together represent a C1C4 alkylene group, K4 represents a hydrogen atom or C1C4 alkyl, K5 represents a hydrogen atom, K51 denotes a hydrogen atom, or in which K5 and K51 together denote an additional bond, K6 is O-K7, 8-K8, C (O) -K9, CH2K10 or O-8 (O) ₂ -K11, where K7 is C3-C7 cycloalkyl, C3C7 cycloalkylmethyl, aryl or phenyl C1-C4 alkyl, R8 represents a hydrogen atom, C1C ₄ alkyl, C1C ₄ alkylcarbonyl, trifluoromethyl, difluoromethyl, trichloromethyl or phenyl, R9 is _C1-C4 alkyl, 1pirrolidinil, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, 4-morpholinyl or aryl, K10 is hydroxyl, halogen, cyano, carboxyl, C1-C4 alkoxy, phenoxy, C 1 -C 4 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-S4alkilaminokarbonil, Ν (Κ15) Κ16 or _C1-C4 alkylcarbonylamino, and K11 is C1-C4 alkyl, amino, mono or di-C ₁ -C ₄ alkylamino or aryl, aryl is phenyl, pyridyl or K12-substituted phenyl, where K12 is hydroxyl, halogen, carboxyl, nitro, amino, cyano, C ₁ -C 4 alkyl, trifluoromethyl, C1-C4alkoxy, S1S4alkoksikarbonil, C1-S4alkilkarbonilaminogruppu, C1-S4alkilkarboniloksi or aminocarbonyl, K13 represents a hydrogen atom, hydroxyl, a halogen atom, a cyano, nitro, amino group, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy, fully or predominantly fluoro-substituted C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl, C (O) OK14, С (ОЖК15) К16, Ν (Κ17) Κ18, 8 (О) ₂ -К19, 8 (О) ₂ -И (К15) К16 or has one of the values К6, where K14 is a hydrogen atom, C1C4 alkyl, C3-C7 cycloalkyl or C3C7 cycloalkylmethyl, K15 is a hydrogen atom, C1-4 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkylmethyl, K16 is a hydrogen atom, C1-4 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylmethyl or aryl, or when K15 and K16 together and including the nitrogen atom to which they are bonded, represent 147 pyrrolidinyl, 1-piperidinyl, 1 piperazinyl, 4-methylpiperazin-1-yl, 1-hexahydroazepinyl or 4-morpholinyl radical, K17 is hydrogen, C1C ₄ alkyl, 8 (O) -K19 ₂ or 8 (O) ₂ -aryl, K18 is C1-C4alkyl, C1C ₄ alkylcarbonyl, 8 (OH) ₂ or 8 -K19 (O) ₂ -aryl, and K19 is C1-C4 alkyl, K20 denotes a hydrogen atom, hydroxyl, halogen atom, nitro, amino group, C1-4 alkyl, trifluoromethyl, C1-C4 alkoxy, fully or predominantly fluoro-substituted C1-C4 alkoxy, C3-C7 cycloalkoxy, C3-C7 cycloalkylmethoxy, CH ₂ -C10, carboxyl, ₁ C1-C4 alkylcarbonyloxy, C ₁ -C ₄ alkylcarbonylamino group or aminocarbonyl, as well as salts, окс-oxides and salts of Ν-oxides of these compounds. 6. The compounds according to claim 1 of formula I, in which K1 is C1-C2 alkoxy, K2 is C1-C2 alkoxy, K3, K31, K4, K5 and K51 denote hydrogen atoms, K6 is O-K7, 8-K8, C (O) -K9, CH ₂ K10 or O-8 (O) ₂ -K11, where K7 is cyclopentyl, cyclopropylmethyl, phenyl, benzyl or phenethyl, K8 is phenyl, K9 is methyl, 1-piperidinyl or phenyl, K10 represents a halogen atom, methoxycarbonyl, morpholin-4-yl or 1methylpiperazin-4-yl, and K11 is methyl or 4-methylphenyl, and in which either K13 is a hydrogen atom or methoxy, and K20 is a hydrogen atom, or K13 is a hydrogen atom, and K20 is cyclopropylmethoxy, as well as salts, β-oxides and salts of β-oxides of these compounds. 7. The compounds of formula I according to one of claims 1, 2, 3, 4, 5 or 6, in which positions 4a and 10b correspond to the same absolute configuration as for the compound (-) - cis-1,2dimethoxy-4- (2-aminocyclohexyl) benzene, which can be used as a starting product and is characterized by optical rotation [a] _with ²⁰ = -58.5 ° (c = 1, ethanol). 8. The use of compounds of formula I according to claim 1 in the treatment of diseases of the respiratory tract, diseases of the arthritic type, diseases of the immune system and dermatoses. 9. A medicine comprising at least one compound of formula I according to claim 1 together with pharmaceutical excipients and / or carriers. 10. The use of compounds of formula I according to claim 1 in the preparation of drugs for the treatment of diseases of the respiratory tract.